Compositions containing 2-(6&#39;-substituted-2&#39;-naphthyl)acetic acid esters used for treating inflammation, pain or pyrexia

ABSTRACT

Compositions containing 2-(6&#39;-substituted-2&#39;-naphthyl)acetic acid derivatives substituted at the 2-position of the acetic acid moiety with methyl, ethyl, difluoromethyl, or methylene, and the salts and esters thereof, having anti-inflammatory, analgesic and anti-pyretic activities, and methods for the use thereof in the treatment of inflammation, pain and pyrexia.

This application is a continuation of application Ser. No. 394,751,filed Sept. 6, 1973 now abandoned, which is a continuation-in-partapplication of U.S. patent applications Ser. Nos. 195,869, 195,877, and195,878, all filed Nov. 4, 1971, and U.S. patent application Ser. No.372,028, filed June 21, 1973; application Ser. No. 195,869, nowabandoned, being, in turn, a divisional application of U.S. patentapplication Ser. No. 810,014, filed Mar. 24, 1969, now abandoned;application Ser. No. 195,877, now abandoned, being, in turn, adivisional application of U.S. patent application Ser. No. 810,013,filed Mar. 24, 1969, now abandoned; application Ser. No. 195,878 being,in turn, a divisional application of U.S. application Ser. No. 694,771,filed Dec. 7, 1967, now abandoned; application Ser. No. 372,028 being acontinuation application of application Ser. No. 176,740, filed Aug. 31,1971, now abandoned, which, in turn, is a continuation-in-partapplication of the aforesaid applications Ser. Nos. 694,771, 810,013,and 810,014; the aforesaid application Ser. No. 694,771 being, in turn,a continuation-in-part application of U.S. application Ser. No. 608,997,filed Jan. 13, 1967, now abandoned; applications Ser. Nos.810,013 and810,014 being, in turn, continuation-in-part applications of aforesaidapplications Ser. Nos. 608,997 and 694,771.

This invention relates to novel compositions containing2-(6'-substituted-2'-naphthyl)acetic acid derivatives, or salts oresters thereof, and the use thereof in the treatment of inflammation,pain and pyrexia.

The compositions of this invention consist essentially of thecombination of a pharmaceutically acceptable non-toxic excipient and atherapeutically effective amount of a carboxylic acid or carboxylic acidester represented by the following formula, or a pharmaceuticallyacceptable salt of a carboxylic acid represented by the followingformula: ##STR1## In the above formula,

R¹ is alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to7 carbon atoms, alkoxymethyl having from 2 to 7 carbon atoms,trifluoromethyl, vinyl, ethynyl, chloro, fluoro, acetyl, hydroxymethyl,formyl, alkoxy having from 1 to 6 carbon atoms, difluoromethoxy,alkoxymethyloxy having from 2 to 7 carbon atoms, alkylthiomethyloxyhaving from 2 to 7 carbon atoms, alkylthio having from 1 to 6 carbonatoms, alkoxymethylthio having from 2 to 7 carbon atoms,alkylthiomethylthio having from 2 to 7 carbon atoms, cyano,difluoromethylthio, or phenyl or alkyl-substituted phenyl having from 6to 8 carbon atoms;

one of R² and R³ is hydrogen, the other being methyl, ethyl ordifluoromethyl or R² and R³ together are methylene;

R⁴ is hydrogen, alkyl having from 1 to 22 carbon atoms, unsaturatedalkyl having from 2 to 22 carbon atoms, cycloalkyl having from 4 to 12carbon atoms, cycloalkylmethyl having from 4 to 9 carbon atoms,2-cycloalkylethyl having from 5 to 10 carbon atoms, 3-cyclopentylpropyl,3-cyclohexylpropyl, aryl or alkyl-substituted aryl having from 6 to 8carbon atoms, benzyl, 2-phenylethyl or 3-phenylpropyl.

Preferably, the 6'-substituent (represented by R¹ in the above formula)is methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, vinyl,ethynyl, fluoro, chloro, methoxy, ethoxy, methoxymethyloxy,difluoromethoxy, methylthio, ethylthio, methoxymethylthio,difluoromethylthio or phenyl; one of R² and R³ is hydrogen and the otheris methyl; and R⁴ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl,pentyl, isopentyl, hexyl, 2-hexyl, isohexyl, heptyl, isoheptyl, octyl,isooctyl, nonyl, isononyl, decyl, isodecyl, undecyl, dodecyl, tridecyl,tetradecyl, pentadecyl, hexadecyl, cyclopentyl or cyclohexyl.

The term "alkyl" refers to and includes branched and straight chainhydrocarbons. Typical alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, tertiary butyl, neopentyl, isopentyl, hexyl, octyl,nonyl, isodecyl, 6-methyldecyl, tridecyl, isotetradecyl, pentadecyl,isohexadecyl, heptadecyl, eicosyl, docosyl, and the like. The term"unsaturated alkyl" refers to unsaturated hydrocarbon groups such asvinyl, allyl, propenyl, crotyl, isopropenyl, 2-propynyl, 1-propenyl,2-butenyl, 1,3-butadienyl, 2-pentenyl, 2-penten-4-ynyl and the like.

The term "cycloalkyl" refers to cyclo hydrocarbon groups such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "alkoxy" refers to straight or branched chain alkyl ethergroups such as methoxy, ethoxy, 2-propoxy, butoxy, 3-pentoxy and thelike.

The term "alkoxymethyloxy" refers to methyl ether groups substitutedwith one alkoxy group (defined above) such as methoxymethyloxy,ethoxymethyloxy, isopropoxymethyloxy and the like.

The term "alkylthio" refers to straight or branched chain alkylthioether groups such as methylthio, ethylthio, propylthio, 2-propylthio,2-butylthio, pentylthio, 3-hexylthio and the like.

The term "alkylthiomethyloxy" refers to methyl ether groups substitutedwith an alkylthio group (defined above) such as methylthiomethyloxy,2-propylthiomethyloxy, pentylthiomethyloxy and the like.

The term "alkylthiomethylthio" as used herein denotes methylthio ethergroups substituted with an alkylthio group such as methylthiomethylthio,ethylthiomethylthio and the like.

The term "alkoxymethylthio" refers to methylthio ether groupssubstituted with an alkoxy group such as methoxymethylthio,ethoxymethylthio, 2-propoxymethylthio and the like.

The term "aryl" refers to phenyl, or o-, m- and/or p-alkyl-substitutedphenyl derivatives such as phenyl, o-tolyl, m-tolyl, p-tolyl,o-ethylphenyl, m-ethylphenyl, p-ethylphenyl, xylyl and the like.

The term "cycloalkylmethyl" refers to cycloalkyl substituted methylgroups such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cycloheptylmethyl, and the like. The term"2-cycloalkylethyl" refers to an ethyl group substituted at the2-position with a cycloalkyl group such as 2-cyclopropylethyl,2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl and2-cycloheptylethyl.

The term "pharmaceutically acceptable salts" refers to salts preparedfrom pharmaceutically acceptable non-toxic bases including inorganicbases and organic bases. Salts derived from inorganic bases includesodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, zinc,manganous, aluminum, ferric, manganic salts and the like. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, tertiary and quaternary amines, substitutedamines including naturally occurring substituted amines, cyclic aminesand basic ion exchange resins, such as triethylamine, tripropylamine,2-dimethylaminoethanol, 2-diethylaminoethanol, ethanolamine, lysine,arginine, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine,choline, betaine, ethylenediamine, glucosamine, methylglucamine,theobromine, purines, piperazine, piperidine, polyamine resins and thelike.

When one of R² and R³ is hydrogen and the other is methyl, ethyl ordifluoromethyl, the compounds of Formula I exist as pairs ofenantiomorphs. Each enantiomorph or optical isomer and mixtures thereofare included within the present invention. The compounds of Formula Iwhich exist as pairs of enantiomorphs can be administered as racemicmixtures or they can be administered as resolved enantiomorphs. In someinstances, one enantiomorph exhibits greater anti-inflammatory,analgesic and/or anti-pyretic activity than the other correspondingenantiomorph.

The optical isomers can be resolved by conventional means, such asselective biological degradation or by the preparation ofdiastereo-isomer salts of the carboxylic acid with an optically activeamine base such as cinchonidine and separating the diastereo-isomers byfractional crystallization. The separated diastereo-isomer salts arethen cleaved to yield the respective optical isomers.

The compounds of Formula I exhibit anti-inflammatory, analgesic andanti-pyretic activities. According, the compositions of this inventionare useful in the treatment and elimination of inflammation such asinflammatory conditions of the muscular skeletal system, skeletal jointsand other tissues, for example, in the treatment of inflammatoryconditions such as rheumatism, concussion, laceration, arthritis, bonefractures, post-traumatic conditions, and gout. In those cases in whichthe above conditions include pain and pyrexia coupled with inflammation,the instant compounds are useful for the relief of these conditions aswell as the inflammation.

Administration of the active compound of Formula I in an appropriatepharmaceutical composition can be via any of the accepted modes ofadministration of agents for the treatment of inflammation, pain, orpyrexia. Thus, administration can be, for example, orally, parenterally,per os, or topically, in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquid solutions, suspensions, creams, lotions, ointments, orthe like, preferably in unit dosage forms suitable for simpleadministration of precise dosages. The compositions of this inventionwill include a conventional pharmaceutical carrier or excipient and anactive compound of Formula I, and, in addition, may include othermedicinal agents, pharmaceutical agents, carriers, adjuvants, etc.

The preferred manner of administration is oral using a convenient dailydosage regimen which can be adjusted according to the degree ofaffliction. Generally, a daily dose of from 0.1 mg. to 30 mg. of theactive compound of Formula I per kilogram of body weight is used. Mostconditions respond to treatment comprising a dosage level of the orderof 1 mg. to 10 mg. per kilogram of body weight per day. For such oraladministration, a pharmaceutically acceptable non-toxic composition isformed by the incorporation of any of the normally employed excipients,such as, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saacharin, talcum, cellulose,glucose, sucrose, magnesium carbonate, and the like. Such compositionstake the form of solutions, suspensions, tablets, pills, capsules,powders, sustained release formulations and the like.

The active compound of Formula I may be formulated into a suppositoryusing, for example, polyalkylene glycols, for example, propylene glycol,as the carrier. Liquid pharmaceutically administerable compositions can,for example, be prepared by dissolving, dispersing, etc. an activecompound of Formula I and optional pharmaceutical adjuvants in acarrier, such as, for example, water, saline, aqueous dextrose,glycerol, ethanol, and the like, to thereby form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amount of non-toxic auxiliarysubstances such as wetting or emulsifing agents, pH buffering agents andthe like, such as for example, sodium acetate, sorbitan monolaurate,triethanolamine oleate, etc.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania,14th. Edition, 1970. The composition to be administered will, in anyevent, contain a quantity of the active compound(s) in apharmaceutically effective amount for relief of the particular conditionbeing treated in accordance with the teachings of this invention.

The compounds of Formula I can be prepared from known startingcompounds. For example, one such method by which they can be preparedinvolves the reaction of a substituted naphthalene with acetyl chloridein nitrobenzene in the presence of about three molar equivalents ofaluminum chloride to afford the corresponding 2-acetylnaphthalenederivative. The resulting derivative is heated with morpholine in thepresence of sulfur at 150° C.; the resulting product is refluxed withconcentrated hydrochloric acid or alcoholic sodium hydroxide followed byacidification to furnish the corresponding 2'-naphthylacetic acidderivative.

The naphthalenes that are used in the above process can be illustratedby the following formula: ##STR2## wherein R¹ is as defined above.

Certain of the naphthalenes of Formula A are known to the art. Forexample, the 2-chloro, 2-fluoro, 2-iodo, 2-methoxy, 2-ethoxy, and2-methylthio naphthalenes are known compounds. The 2-alkoxy and2-alkylthio naphthalenes having more than 1 or 2 carbon atoms in thesubstituent at the 2-position can be made by processes analogous to theknown processes for producing the 2-methoxy(or 2-ethoxy) or 2-methylthionaphthalenes, respectively. Moreover the compounds of Formula A can beprepared by other conventional means. For example, methoxybenzene istreated with succinic anhydride and aluminum chloride in a hydrocarbonsolvent to afford 4-(4'-methoxyphenyl)-4-oxobutanoic acid. This isreduced by treatment with sodium borohydride and hydrogenolyzed bytreating with palladium-on-charcoal catalyst and hydrogen to furnish4-(4'-methoxyphenyl)butanoic acid. The corresponding acid chloride canbe prepared by treatment with thionyl chloride, and the acid chloride istreated with aluminum chloride to afford 7-methoxy-1-tetralone. Thetetralone is reduced and hydrogenolyzed by the means described above tofurnish 6-methoxytetralin which is dehydrogenated by treating withpalladium-on-charcoal catalyst to afford 2-methoxynaphthalene. Byutilizing methylbenzene in the above process, 7-methyl-1-tetralone (asan intermediate) and 2-methylnaphthalene is prepared.

2-Alkyl, 2-cycloalkyl, or 2-aryl substituted naphthalenes of Formula Awherein R¹ is alkyl or aryl can be prepared from 2-tetralone by treatingthe latter with an equivalent of an alkyl, cycloalkyl or aryl magnesiumbromide in an ether to obtain the corresponding 2-alkyl-, 2-cycloalkyl-,or 2-aryl-3, 4-dihydronaphthalene which is dehydrogenated by heatingwith palladium charcoal catalyst to afford the corresponding 2-alkyl,2-cycloalkyl, or 2-arylnaphthalenes.

2-Vinylnaphthalenes are prepared by refluxing 2-ethylnaphthalene with amolar equivalent of N-bromosuccinimide in a halohydrocarbon solvent,such as chloroform, methylene chloride, dichloroethane, carbontetrachloride, 1,4-dichlorobutane, chlorobenzene, chloroethane,chlorocyclohexane, dichlorobenzene, and the like, in light and in thepresence of a trace amount of perioxide, such as benzoyl peroxide,t-butyl peroxide, peroxyacetic acid, and the like, to afford thecorresponding 2-(1'-bromoethyl)naphthalene. The latter isdehydrobrominated by treating with lithium carbonate indimethylformamide to afford 2-vinylnaphthalene.

2-Ethynylnaphthalene is prepared from 2-vinylnaphthalene by brominatingthe latter in a halohydrocarbon solvent and then dehydrobrominating theresulting 2-(1',2'-dibromoethyl)naphthalene by conventional means, suchas by treatment with sodium amide in liquid ammonia, to furnish the2-ethynylnaphthalene.

2-Cyclopropylnaphthalene is prepared from 2-vinylnaphthalene byrefluxing in ether with diiodomethane in the presence of zic:coppercouple.

2-Cyclobutylnaphthalene is prepared from 2-naphthylmagnesium bromide bytreating the latter with cyclobutanone to furnish2-(1'-hydroxycyclobutyl)naphthalene, which is hydrogenolyzed withhydrogen in the presence of Raney nickel to furnish2-cyclobutylnaphthalene.

2-Cyclopentylnaphthalene can be prepared by heating naphthalene withcyclopentyl benzenesulfonate. 2-Cyclohexylnaphthalene can be similarlyprepared by employing cyclohexyl benzenesulfonate.

2-Acetylnaphthalene is prepared by treating2-(1'-bromoethyl)naphthalene, prepared as described above, wtih sodiumacetate in acetic acid to afford 2-(1'-acetonyethyl)naphthalene whichupon base hydrolysis furnishes the 2-(1'-hydroxyethyl)naphthalene. Thelatter is oxidized with an equivalent of chromium trioxide in glacialacetic acid, or 8N sulfuric acid and acetone to furnish2-acetylnaphthalene. 2-Carboxynaphthalene is prepared from2-acetylnaphthalene by treating the latter with aqueous sodiumhypochlorite. The 2-carboxynaphthalene is treated with diborane in anether, such as diglyme (diethyleneglycol dimethyl ether), to yield2-hydroxymethylnaphthalene.

The 2-hydroxymethyl group is etherified to form alkoxymethyl groups byconventional means employed to etherify primary hydroxy groups.

2-Formylnaphthalene is prepared from 2-hydroxymethylnaphthalene bytreating the latter with manganese dioxide in a halohydrocarbon solvent.

2-Cyanonaphthalene is prepared by refluxing 2-formylnaphthalene withhydroxylamine hydrochloride and sodium acetate in ethanol to furnish thecorresponding oxime which is refluxed with acetic anhydride in thepresence of an acid catalyst to furnish 2-cyanonaphthalene.

Alternatively, the above substituents can be introduced on anaphthylacetic acid ester derivative by using an ethyl or vinylsubstituted naphthylacetic acid ester derivative as a starting material.

Preferably, the trifluoromethyl, difluoromethoxy, difluoromethylthio,alkoxymethyloxy, alkoxymethylthio, alkylthiomethyloxy andalkylthiomethylthio groups are introduced on the 2-naphthylacetic acidderivatives as one of the final steps.

Another method of preparing the 6'-substituted-2'-naphthylacetic acidsor esters thereof employs substituted 1-tetralones as the staringmaterials. tThis method can be illustrated by the following reactionsequence: ##STR3## wherein R¹¹ represents the groups represented by R¹and additionally a hydroxy group.

The 1-tetralones, the compounds of Formula C, are heated with two ormore equivalents of a dialkyl carbonate, such as diethyl carbonate, inthe presence of one or more equivalents of an alkali metal hydride, suchas sodium hydride, potassium hydride, and the like, in a hydrocarbonsolvent, such as hexane, cyclohexane, heptane, isooctane, benzene,toluene, xylene, and the like, to afford the corresponding alkoxycarbonyl compounds of Formula D. The latter are treated with an alkalimetal hydride in a hydrocarbon solvent; the resulting products aretreated with an α-haloacetic acid ester such as ethyl α-bromoacetate,methyl α-iodoacetate, and the like, to furnish the corresponding2-alkoxycarbonyl-2-(alkoxycarbonylmethyl)-1-tetralones of Formula E. Thelatter are hydrolyzed with an acid, such as hydrochloric acid, sulfuricacid, p-toluenesulfonic acid, and the like to obtain the2-(carboxymethyl) compounds of Formula F. The latter are reduced with areducing agent, such as sodium borohydride, lithium borohydride; or withone equivalent of hydrogen in the presence of Adam's catalyst, and thelike, to afford the hydroxy compounds of Formula G which arehydrogenolyzed by treatment with an equivalent amount of hydrogen in thepresence of a hydrogenation catalyst, such as platinum, palladium, andthe like, to furnish the corresponding1,2,3,4-tetrahydro-2-naphthylacetic acid derivatives of Formula H. Thecompounds of Formula H are esterified by conventional means, such as themeans described above, to afford the compounds of Formula J; these aredehydrogenated by heating with palladium-on-charcoal catalyst attemperatures of 180° C and higher to furnish the corresponding2-naphthylacetic acid ester derivatives, the compounds of Formula K. Thelatter compounds are hydrolyzed to the corresponding 2-naphthylaceticacid derivatives, the compounds of Formula L, by conventionalhydrolysis, such as by treatment with an aqueous methanolic 5percentsodium hydroxide solution, followed by acidification.

By treating the compounds of Formula D with an alkali metal hydride andthen with an α-halocarboxylic acid ester, such as methylα-bromopropionate and the like, the corresponding2-alkoxycarbonyl-2-(1'-alkoxycarbonylalkyl)-1-tetralones are obtained.These compounds can be hydrolyzed, reduced, hydrogenolyzed, esterified,dehydrogenated and hydrolyzed by the means used to similarly treatcompounds of Formula E, to obtain the corresponding2-(2'-naphthyl)propionic acid derivatives.

The 1-tetralones of Formula C can be prepared directly from naphthalenesby conventional means known to the art. For example, the substituted1-tetralones can be prepared from substituted naphthalenes. Thesubstituted naphthalenes are reduced with 2 molar equivalents ofhydrogen in the presence of a platinum, palladium, nickel catalyst, orthe like, to afford the corresponding substituted tetralin. Thesubstituted tetralin is then oxidized, such as with chromium trioxide inglacial acetic acid to obtain the substituted 1-tetralone.

The 1-tetralones substituted at position 6 of Formula C can also beprepared from the corresponding 7-substituted-1-tetralones (which areintermediates in the above-described preparation of naphthalenessubstituted at position 6) by reducing and hydrogenolyzing the latterwith sodium borohydride and hydrogen in the presence of palladiumrespectively to afford the corresponding tetralins. The tetralins arethen oxidized with chromium trioxide in acetic acid to afford thecorresponding 1-tetralones substituted at position 6. The tetralones areseparated by conventional means, such as fractional crystallization ordistillation.

Another method by which the present compounds can be prepared involvesthe reaction of 2-tetralones with one or more equivalents of a1-alkoxycarbonylalkylidene triphenyl phosphorane, such as1-methoxycarbonylethylidene triphenyl phosphorane, to furnish thecorresponding 2,2-(1'-alkoxycarbonylalkylidene)tetralin. The latter uponheating with palladium-on-charcoal catalyst affords the corresponding2-naphthylacetic acid ester derivative. The 1-alkoxycarbonylalkylidenetriphenyl phosphorane reactant is obtained by reactingtriphenylphosphine with a 2-halocarboxylic acid ester in an organicreaction medium followed by reaction with a base.

Thus, for example, by reacting 6-methoxy-2-tetralone with thetriphenylphosphorane derived from ethyl 2-halopropionate,2-(1'-carbethoxyeth-1'-ylidene)-6-methoxytetralin is prepared.Dehydrogenation of the latter compound provides ethyl2-(6'-methoxy-2'-naphthyl)propionate which upon hydrolysis affords2-(6'-methoxy-2'-naphthyl)propionic acid.

Substituted 2-tetralones of the following formula can be utilized in theabove process: ##STR4## wherein R¹¹ is as defined above.

The substituted 2-tetralones of Formula N are prepared by treating thecorresponding 1-tetralones with butylnitrite and hydrogen chloride gasin ether and then reacting the resulting 2-oximino-1-tetralones with anacid anhydride, such as acetic anhydride, in an organic acid, such asacetic acid in the presence of hydrogen and palladium-on-carbon catalystto obtain the substituted 2-acetylamino-1-tetralone. The keto groups arethen reduced to hydroxy groups with sodium borohydride or the like. Thesubstituted 2-acetylamino-1-hydroxytetralines are then treated withglacial acetic acid in the presence of concentrated acid to obtain thecorresponding substituted 2-tetralones of Formula N.

The addition of an alkyl substituent at the α-position of the aceticacid group to obtain the 2-(2'-naphthyl)propionic acid derivatives canbe represented by the following: ##STR5## wherein R¹¹ is as previouslydefined.

The 2-naphthylacetic acid derivatives of Formula P are esterified byconventional means, such as by reaction with an alkanol in the presenceof boron trifluoride, to afford the corresponding esters of Formula Q.The compounds of Formula Q are treated with an alkali metal hydride suchas sodium hydride, potassium hydride, and the like, in an ether solvent,such as monoglyme, and then with an alkyl halide, such as methyl iodide,to afford the corresponding 2-(6'-substituted-2'-naphthyl)-α-alkylaceticacid ester derivatives of Formula R, such as, for example, the2-(6'-substituted-2'-naphthyl)propionic acid esters. These derivativescan be hydrolyzed by refluxing in a basic solution to obtain thecorresponding 2-(6'-substituted 2'-naphthyl)-α- alkylacetic acidderivatives, such as, for example, the2-(6'-substituted-2'-napththyl)propionic acids.

The 2-(6'-ethynyl-2'-naphthyl)propionic acid derivatives can be preparedfrom 2-(6'-vinyl-2'-naphthyl)propionic acid derivatives by brominatingand dehydrobrominating the vinyl group as described above.

The α-difluoromethyl group can be introduced in the acetic acid moietyby treating the 2-naphthylacetic acid ester derivatives with an alkalimetal or alkali metal hydride in a dialkyl carbonate, such as diethylcarbonate, to afford the corresponding 2-alkoxy-carbonyl derivatives.The latter is treated with chlorodifluoromethane and an alkali metalalkoxide, such as potassium t-butoxide, in an ether solvent, preferably1,2-dimethoxyethane to afford the corresponding2-alkoxycarbonyl-2-difluoromethyl derivatives, which are hydrolyzed tofurnish the corresponding 2-(2'-naphthyl)-2-carboxy-3,3-difluoropropionic acid derivatives. The deesterified product isdecarboxylated by heating to between 30° C. and 150° C., until theevolution of carbon dioxide ceases, to give the corresponding2-(2'-naphthyl)-3, 3-difluoropropionic acid derivatives.

By treating the above 2'-naphthyl-2-alkoxycarbonylacetic acid esterderivatives with an equivalent of an alkali metal hydride in ahydrocarbon solvent, then with an alkyl halide, the corrresponding2-(2'-naphthyl)-2-alkoxycarbonylalkanoic acid ester derivatives areobtained. The latter are hydrolyzed and decarboxylated to furnish thecorresponding 2-(2'-naphthyl)propionic acid derivatives. This is analternative method of introducing the α-alkyl substituent on the aceticacid moiety.

The α,α-methylene group is introduced by treating a2-(6'-substituted-2'-naphthyl)acetic acid alkyl ester derivative withformaldehyde or paraformaldehyde and an alkali metal alkoxide, such assodium methoxide, in dimethylsulfoxide.

In the preferred embodiment of this invention the hydroxymethyl, thealkoxymethyloxy, alkylthiomethyloxy, alkoxymethylthio andalkylthiomethylthio are introduced after the introduction ofsubstituents on the acetic acid moiety of the 2'-naphthylacetic acidderivatives.

Those compounds having a trifluoromethyl group can be fprepared from thecorresponding 6'-iodo compounds (Formula I, R¹ is iodo). The2-(6'-iodo-2'-naphthyl)acetic acid derivatives by reaction with sulfonylchloride are converted to the corresponding acid chloride, which isconverted to the corresponding amide by reaction with an amine.Treatment of the amide wih trifluoromethyl iodide in the presence ofcopper at elevated temperatures yields the corresponding6'-trifluoromethyl compound which is then treated with acid to yield thecorresponding 2-(6'-trifluoromethyl-2'-naphthyl)acetic acid derivative.

Those compounds containing a trifluoromethyl group can also be preparedfrom the corresponding 6'-methylsubstituted 2'-naphthylacetic acid esterderivatives by treating the latter with chlorine and phosphorustrichloride in the presence of light to afford the correspondingtrichloromethyl derivatives, which, when refluxed with antimonytrifluoride in a hydrocarbon solvent, furnish the corresponding6'-trifluoromethyl 2'-naphthylacetic acid ester derivatives.

Those compounds having a 6-hydroxy group are preferably prepared fromthe corresponding 6'-alkoxy-2'-naphthylacetic acid ester derivatives byrefluxing the latter with 48 percent hydrobromic acid in acetic acid tofurnish the free hydroxy derivative. This, in turn, can be treated withchlorodifluoromethane and an alkali metal hydroxide in aqueous dioxaneor tetrahydrofuran, to afford the corresponding6'-difluoromethoxy-2'-naphthylacetic acid derivatives. By utilizing a2-(6'-methylthio-2'-naphthyl)acetic acid alkyl ester derivative in theabove process, the corresponding2-(6'-difluoromethylthio-2'-naphthyl)acetic acid alkyl ester derivativeis obtained.

By utilizing 6'-alkylthio-2'-naphthylacetic acid ester derivatives inthe above process preferably replacing the hydrobromic acid and aceticacid with cyanogen bromide, the corresponding 6'-difluoromethylthioderivatives are obtained.

The hydroxy groups are etherified by conventional methods, for example,by treatment with an alkali metal hydride and then with an alkylhalide,preferably an alkylbromide or iodide; or by treatment with a diazoalkaneor an alkanol in the presence of boron trifluoride in an ether solvent,and the like.

The alkoxymethyloxy groups are introduced by treating the6'-hydroxy-2'-naphthylacetic acid derivatives with analkoxychloromethane in dimethylformamide to afford the corresponding6'-alkoxymethyloxy-2'-naphthylacetic acid derivatives. The6'-alkylthiomethyloxy-2'-naphthylacetic acid derivatives are prepared byutilizing an alkylthiochloromethane in the above process.

The 6'-alkoxymethylthio-2'-naphthylacetic acid derivatives are preparedby refluxing 6'-thio-2'-naphthylacetic acid derivatives with analkoxychloromethane in dimethylformamide. The 6'-alkylthiomethylthioderivatives are prepared by using an alkylthiochloromethane in place ofalkoxychloromethane in the above process.

The foregoing general procedures are useful for the preparation of theother naphthylacetic acid derivatives hereof.

Upon their preparation, the naphthylacetic acid derivatives can beconverted to the corresponding esters and acid addition salts thereof.

The salt derivatives of the compounds of Formula I are prepared bytreating the corresponding free acids of the compounds of Formula I(wherein R⁴ is hydrogen) with at least one molar equivalent of apharmaceutically acceptable base. Representative pharmaceuticallyacceptable bases are sodium hydroxide, potassium hydroxide, lithiumhydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide,ferrous hydroxide, zinc hydroxide, manganous hydroxide, aluminumhydroxide, ferric hydroxide, manganic hydroxide trimethylamine,triethylamine, tripropylamine, 2-dimethylaminoethanol,2-diethylaminoethanol, arginine, lysine, histidine, caffeine, procaine,N-ethylpiperdine, hydrabamine, choline betaine, ethylenediamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, polyamine resins and the like. The reaction is conducted inwater, alone or in combination with an inert, water-miscible organicsolvent, at a temperature of from about 0° C. to about 100° C.,preferably at room temperature. Typical inert, water-mixcible organicsolvents include methanol, ethanol, isopropanol, butanol, acetone,dioxane or tetrahydrofuran. The molar ratio of compounds of Formula I tobase used are chosen to provide the ratio desired for any particularsalt. For preparing, for example, the calcium salts or magnesium saltsof the compounds of Formula I, the free acid starting material can betreated with at least one molar equivalent of pharmaceuticallyacceptable base to yield a neutral salt. When the aluminum salts of thecompounds of Formula I are prepared, at least one molar equivalent ofthe pharmaceutically acceptable base are employed if a neutral saltproduct is desired.

In the preferred procedure, the calcium salts and magnesium salts of thecompounds of Formula I can be prepared by treating the correspondingsodium or potassium salts of the compound of Formula I with at least onemolar equivalent of calcium chloride or magnesium chloride,respectively, in an aqueous solution, alone or in combination with aninert water-miscible organic solvent, at a temperature of from about 20°C. to about 100° C. Preferably, the aluminum salts of the compounds ofFormula I can be prepared by treating the corresponding free acids ofthe compounds of Formula I with at least one molar equivalent of analuminum alkoxide, such as aluminum triethoxide, aluminum tripropoxideand the like, in a hydrocarbon solvent, such as benzene, xylene,cyclohexane, and the like at a temperature of from 20° C to about 115°C. Similar procedures can be used to prepare salts of inorganic baseswhich are not sufficiently soluble for easy reaction.

The salt products are isolated by conventional means. For example, thereaction mixtures are evaporated to dryness, and the salts can befurther purified by conventional methods.

The esters of Formula I are prepared by esterifying the corresponding2-(6'-substituted-2'-naphthyl)acetic acid derivatives (wherein R⁴ ishydrogen) with an alcohol reagent corresponding to the desired ester,e.g. an alkanol having up to 22 carbon atoms, an alkenol having up to 22carbon atoms, a cycloalkanol having from 4 to 7 carbon atoms, acycloalkylmethanol having from 4 to 9 carbon atoms, a cycloalkylethanolhaving from 5 to 10 carbon atoms, phenol, an o-, m- and/orp-alkylsubstituted phenol having up to 8 carbon atoms, benzylalcohol,2-phenylethanol, 3-phenylpropanol, 3-cyclopentylpropanol,3-cyclohexylpropanol, etc. This reaction is conducted in the presence ofa strong acid, such as boron trifluoride, hydrogen chloride, sulfuricacid, p-toluenesulfonic acid, and the like. If the alcohol reagent usedin the esterification is a liquid at the reaction temperature, thealcohol reagent can be the reaction solvent. Optionally, the reactioncan be carried out in a non-aqueous liquid inert organic solvent inwhich the 2-(6'-substituted-2'-naphthyl)acetic acid derivative and thealcohol reagent are soluble, such as hydrocarbon solvent like hexane,iso-octane, decane, cyclohexane, benzene, toluene, xylene; a halogenatedhydrocarbon solvent like methylene chloride, chloroform, dichloroethane;or an ether solvent like diethylether, dibutylether, dioxane,tetrahydrofuran. In the case where the alcohol reagent is a solid, thereaction preferably is conducted in a non-aqueous liquid inert organicsolvent. The reaction is conducted at from about 0° C. to the refluxtemperature of the reaction mixture, preferably from 15° C to 35° C.

The product is isolated by conventional means such as diluting thereaction mixture with water, extracting the resulting aqueous mixturewith a water-immiscible inert organic solvent, such as diethyl ether,benzene, methylene chloride, and the like, combining the extracts,washing the extracts with water to neutrality and then evaporating underreduced pressure.

The esters of Formula I can also be prepared by esterifying thecorresponding 2-(6'-substituted-2'-naphthyl)acetyl halide derivativeswith an alcohol reagent. This is the preferred method for preparingtertiary alcohol esters. The 2-(6'-substituted-2'-naphthyl)acetyl halidederivatives are prepared by treating the corresponding2-(6'-substituted-2'-naphthyl)acetic acid derivatives with a thionylhalide, such as thionyl chloride; a phosphorous trihalide such asphosphorous tribromide; or a phosphorous pentahalide such as phosphorouspentachloride; preferably a thionyl halide is employed. The preparationof the 2-(6'-substituted-2'-naphthyl)acetyl halide derivatives isoptionally carried out in an inert organic solvent such as a hydrocarbonsolvent like benzene, toluene, hexane, cyclohexane, and the like; or ahalogenated hydrocarbon like methylene chloride, chloroform, carbontetrachloride, and the like. The reaction is normally performed attemperatures between 0° C and 100° C, preferably between -15° C and 80°C. The acetyl halide products are isolated by conventional means. Forexample, when a thionyl halide is used to prepare the acetyl halidederivative, the reaction mixture is evaporated under reduced pressure toyield the product.

The 2-(6'-substituted-2'-naphthyl)acetyl halide derivatives are treatedwith alcohol reagents to prepare the esters of Formula I. The reactionis generally performed at temperatures between 0° C and the refluxtemperature of the reaction mixture, preferably at room temperature.When the alcohol reagent employed is a liquid at the reactiontemperature, the alcohol reagent can be the reaction solvent.Optionally, the reaction can be carried out in a non-aqueous inertorganic solvent in which the 2-(6'-substituted-2'-naphthyl)acetyl halidederivatives and the alcohol reagents are soluble, such as hydrocarbons,halogenated hydrocarbons, pyridine or mixtures thereof. At least a molarequivalent of the alcohol reagent employed per molar equivalent of the2-(6'-substituted-2'-naphthyl)acetyl halide derivative; and generallymore than one molar equivalent of the alcohol reagent are employed. Theester products are isolated by conventional means. For example, thereaction mixture is diluted with water and extracted with diethyl ether.Ether extracts are combined, washed with water to neutrality, dried andevaporated to yield the compounds of Formulas I and II.

The preferred 2-(6'-substituted-2'-naphthyl)acetic acid esterderivatives are those ester derivatives prepared from methyl alcohol,ethyl, alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol,2-butyl alcohol, pentyl alcohol, 2-pentyl alcohol, isopentyl alcohol,hexyl alcohol, 2-hexyl alcohol, isohexyl alcohol, heptyl alcohol,2-heptyl alcohol, isoheptyl alcohol, octyl alcohol, 2-octyl alcohol,isooctyl alcohol, nonyl alcohol, 2-nonyl alcohol, isononyl alcohol,decyl alcohol 2-decyl alcohol, isodecyl alcohol, undecyl alcohol,dodecyl alcohol, tridecyl alcohol, tetradecyl alcohol, pentadecylalcohol or hexadecyl alcohol.

This invention is further illustrated by the following specific butnon-limiting examples.

PREPARATION 1

A mixture of 12.2 g. of methoxybenzene, 20 g. of succinic anhydride, 27g. of aluminum chloride, and 250 ml. of carbon disulfide is stirred forfour hours; the mixture is poured into 500 g. of ice, and the productsare isolated by extraction with benzene. The product,4-(4'-methoxyphenyl)-4-oxobutanoic acid is reduced with sodiumborohydride, hydrogenolyzed with hydrogen in the presence of palladiumcharcoal catalyst, and cyclized by treatment with concentrated sulfuricacid to afford 7-methoxy-1-tetralone.

Ten grams of the above product is reduced by treatment with 6 g. ofsodium borohydride in ethanol at 25° C for six hours. The mixture isacidified with aqueous 1 N hydrochloric acid and6-methoxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene is isolated by benzeneextraction. The product is hydrogenolyzed with hydrogen in the presenceof palladium-on-carbon catalyst and dehydrogenated by heating with 10percent palladium-on-charcoal catalyst to yield 2-methoxynaphthalene.

By the above procedure, but preferably dehydrogenating with 2equivalents of sulfur at 200° C for one hour, 7-chloro-1-tetralone isprepared from chlorobenzene and is converted to 2-chloronaphthalene.

Likewise, by means of the above process, 7-fluoro-1-tetralone isprepared from fluorobenzene, and 2-fluoronaphthalene is prepared from7-fluoro-1-tetralone.

Similarly, 7-isopropyl-1-tetralone, 7-methylthio-1-tetralone,7-iodo-1-tetralone, 7-bromo-1-tetralone, and 7-methyl-1-tetralone areprepared from the corresponding substituted benzene derivatives by meansof the above process. 2-iodonaphthalene and 2-bromonaphthalene areprepared from 7-iodo-1-tetralone and 7-bromo-1-tetralone, respectively.

PREPARATION 2

A mixture of 15.5 g. of 2-vinylnaphthalene, 23 g. of diiodomethane, 19.6g. of zinc-copper couple (comprising 19.5 g. of zinc and 0.1 g. ofcopper) and 500 ml. of diethyl ether is refluxed for eight hours; thecooled mixture is then filtered, washed with dilute hydrochloric acid,washed with water to neutrality, dried and evaporated to yield2-cyclopropylnaphthalene.

EXAMPLE 3

To a mixture of 23.1 g. of 2-naphthyl magnesium bromide and 250 ml. ofdiethyl ether, 7 g. of cyclobutanone are slowly added. After theaddition, the mixture is refluxed for one hour, cooled, acidified withaqueous hydrochloric acid and filtered. The product was isolated bymethylene chloride extraction to furnish2-(1'-hydroxycyclobutyl)-napthalene. The product is hydrogenated in 200ml. of ethanol with a molar equivalent of hydrogen in the presence of 50g. of Raney nickel; the reaction mixture is filtered after thehydrogenolysis and evaporated to furnish 2-cyclobutylnaphthalene.

PREPARATION 4

To a mixture of 15.5 g. of 2-vinylnaphthalene and 300 ml. of chloroform,a 5 percent bromine in chloroform solution is added at -10° C. until thebromine color persists. The mixture is then added to 200 ml. of ammoniacontaining 15 g. of sodium amide. The mixture is allowed to evaporate,acidified with dilute hydrochloric acid, and the residue is extractedwith diethyl ether. The extracts are combined, washed to neutrality withwater, dried, and evaporated to yield 2-ethynylnaphthalene.

PREPARATION 5

A mixture of 14.6 g. of 2-tetralone, 20 g. of phenylmagnesium bromide,and 200 ml. of diethyl ester is stirred for four hours and then refluxedfor one hour. The mixture is acidified with the addition of 200 ml. of 1N hydrochloric acid, filtered, and extracted with diethyl ether. Theextracts are combined, washed with water to neutrality, filtered, driedand evaporated; unchanged 2-tetralone is removed by distillation. Theresidue, containing 2-phenyl-3,4-dihydronaphthalene is mixed with 25 g.of 5 percent palladium-on-charcoal catalyst; the resulting mixture isheated to 200° C for six hours, cooled, diluted with 250 ml. ofchloroform, filtered, and evaporated to give 2-phenylnaphthalene.

Similarly, 2-p-tolynaphthalene is prepared by using p-tolyl magnesiumbromide is respectively in place of phenylmagnesium bromide in the aboveprocess.

EXAMPLE 1

To a mixture of 1.6 g. of 2-methoxynaphthalene, 1.6 g. of acetylchloride, and 20 ml. of nitrobenzene, 4.0 g. of aluminum chloride areslowly added. The resulting mixture is stirred for 48 hours at 25° C;then it is washed with water until free of chloride. The mixture isdried over sodium sulfate and evaporated under reduced pressure. Theresidue, 2-acetyl-6-methoxynaphthalene, is refluxed in 2 ml. ofmorpholine containing one-half gram of sulfur for two hours; thereaction mixture is then filtered and evaporated. The resultingthioamide derivative is extracted with diethly ether; the extracts arecombined and evaporated. The residue is refluxed in 10 ml. ofconcentrated hydrochloric acid for two hours, cooled to 25° C, and madealkylene with aqueous sodium hydroxide. The mixture is then extractedwith ether and the extracts discarded. The aqueous layer is acidifiedand the precipitated 6-methoxy-2-naphthylacetic acid filtered.

Similarly, 2-naphthylacetic acid, 6-chloro-2-naphthylacetic acid,6-fluoro-2-naphthylacetic acid, 6-ethoxy-2-naphthylacetic acid,6-methyl-2-naphthylacetic acid, 6-ethyl-2-naphthylacetic acid,6-isopropyl-2-naphthylacetic acid, 6-cyclopropyl-2-naphthylacetic acid,6-cyclohexyl-2-naphthylacetic acid, 6-vinyl-2-naphthylacetic acid,6-ethynyl-2-naphthylacetic acid and 6-phenyl-2-naphthylacetic acid areprepared from their respective corresponding naphthalene startingmaterials.

EXAMPLE 2

A mixture of 18 g. of 6-methoxy-1-tetralone, 60 g. of diethyl carbonate,2.5 g. of sodium hydride, and 200 ml. of toluene is heated to 60° C forfive hours. The mixture is cooled, acidified by the addition of 200 ml.of 1 N hydrochloric acid, and then extracted with three 75 ml. portionsof benzene. The extracts are combined, washed with water to neutrality,and dried over sodium sulfate. The mixture, containing6-methoxy-2-ethoxycarbonyl-1-tetralone, is treated with 2.5 g. of sodiumhydride at room temperature with stirring. Twenty grams of ethylα-bromoacetate are then added, and the mixture is allowed to stand for12 hours at room temperature. The mixture is added to 500 ml. of waterand extracted with methylene chloride. The extracts are combined, washedwith water to neutrality, dried over sodium sulfate, and evaporated. Theresidue, containing6-methoxy-2-ethoxycarbonyl-2-(ethoxycarbonylmethyl)-1-tetralone, isrefluxed in 200 ml. of 6 N hydrochloric acid for 24 hours, and themixture is evaporated. The residue, containing6-methoxy-2-(carboxymethyl)-1-tetralone, is reduced by treated it with200 ml. of ethanol containing 8 g. of sodium borohydride. After onehour, the mixture is acidified with the addition of 100 ml. of 3 Nhydrochloric acid, and the resulting mixture is extracted with severalportions of methylene chloride. The extracts are combined, washed withwater to neutrality, dried over sodium sulfate, and evaporated. Theresidue, containing6-methoxy-1-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetic acid, ishydrogenolyzed by hydrogenating with one equivalent of hydrogen inacetic acid containing 300 mg. of 5 percent palladium-on-barium sulfate.The hydrogenation mixture is filtered and evaporated. The residue,containing 6-methoxy-1,2,3,4-tetrahydro-2-naphthylacetic acid, isdissolved in 200 ml. of diethyl ether, and the mixture is added to a 100ml. solution of diethyl ether containing 4 g. of diazomethane. Themixture is then evaporated to dryness. The esterified residue isdehydrogenated by adding it to 1 g. of 10 percent palladium-on-charcoaland heating the resulting mixture for six hours at 200° C. The cooledmixture is diluted with 200 ml. of chloroform, filtered, and evaporatedto afford methyl 6-methoxy-2-naphthylacetate.

Similarly, methyl 6-methyl-2-naphthylacetate, methly6-methylthio-2-naphthylacetate, methyl 6-chloro-2-naphthylacetate, areprepared from 6-methyl-1-tetralone, 6-methylthio-1-tetralone and6-chloro-1-tetralone, respectively, by means of the above process.

A mixture of 25 g. of methyl 6-methoxy-2-naphthylacetate, 15 g. ofsodium carbonate, 200 ml. of methanol, and 25 ml. of water are stirredfor 24 hours. The reaction mixture is then acidified with 200 ml. of 2 Nhydrochloric acid and extracted with methylene chloride. The extractsare combined, washed with water, dried over sodium sulfate, andevaporated to yield 6-methoxy-2-naphthylacetic acid.

Likewise, the methyl-6-substituted-2-naphthylacetates are hydrolyzed tothe corresponding 6-substituted 2-naphthylacetic acid.

EXAMPLE 3

To a mixture of 22 g. of methyl 6-methyl-2-naphthylacetate, 2.5 g. ofsodium hydroxide and 150 ml. of 1,2-dimethoxyethane, 25 g. of methyliodide are added. The reaction mixture is allowed to stand for severalhours and is then diluted with ethanol followed by water and extractedwith methylene chloride. The extracts are combined, washed with water toneutrality, dried over sodium sulfate, filtered, and evaporated to yieldmethyl 6-methyl-2-naphthyl-α-methylacetate. This derivative ishydrolyzed by treatment with sodium carbonate in aqueous methanol, andthe reaction mixture is acidified with hydrochloric acid, washed, driedand evaporated to dryness to yield 2-(6'-methyl-2'-naphthyl)propionicacid.

2-(6'-methyl-2'-naphthyl)butyric acid is prepared by using ethyl iodidein place of methyl iodide in the above process.2-(6'-ethoxy-2'-naphthyl)propionic acid,2-(6'-ethyl-2'-naphthyl)propionic acid,2-(6'-methoxymethyl-2'-naphthyl)propionic acid,2-(6'-trifluoromethyl-2'-naphthyl)propionic acid,2-(6'-isopropyl-2'-naphthyl)propionic acid,2-(6'-vinyl-2'-naphthyl)propionic acid,2-(6'-cyclopropyl-2'-naphthyl)propionic acid,2-(6'-fluoro-2'-naphthyl)propionic acid,2-(6'-chloro-2'-naphthyl)propionic acid,2-(6'-chloro-2'-naphthyl)butyric acid,2-(6'-methoxy-2'-naphthyl)propionic acid,2-(6'-methylthio-2'-napthyl)propionic acid and2-(6'-ethylthio-2'-naphthyl)propionic acid are prepared from thecorresponding methyl 2-naphthylacetate derivatives.

EXAMPLE 4

To a solution of 22.6 g. of 2-(6'-vinyl-2'-naphthyl)propionic acid and100 ml. of chloroform, there are added 320 g. of 5 percent solution ofbromine in chloroform at -10° C. The resulting mixture is allowed tostand for 2 hours. The mixture is then evaporated to dryness. Theresidue is taken up in 250 ml. of diethyl ether and added to a mixtureof liquid ammonia and 8 g. of sodium amide. The resulting ammoniamixture is allowed to stand for 10 hours; the mixture is then evaporatedto dryness. The residue is acidified with dilute hydrochloric acid andextracted with diethyl ether, washed with water to neutrality, driedover sodium sulfate and evaporated to yield2-(6'-ethynyl-2'-naphthyl)propionic acid.

In a similar manner, 2-(6'-ethynyl-2'-naphthyl)-2,2-difluoromethylacetic acid is prepared from 2-(6'-vinyl-2'-naphthyl)-2,2-difluoromethylacetic acid by means of the above process.

EXAMPLE 5

A mixture of 22 g. of methyl 6-fluoro-2-naphthylacetate, 10 g. of sodiummethoxide, 6 g. of paraformaldehyde, and 200 ml. of dimethylsulfoxide isstirred for 18 hours at 25° C; the reaction mixture is acidified by theaddition of 250 ml. of 1 N hydrochloric acid and extracted withmethylene chloride. The extracts are combined, washed, dried, filtered,and evaporated to yield methyl 2-(6'-fluoro-2'-naphthyl)acrylate whichis purified by chromatographing on alumina, eluting withmethanol-diethyl ether. The product is hydrolyzed with sodium carbonatein aqueous methanol and the reaction mixture acidified with hydrochloricacid, filtered, washed with water, dried and evaporated to dryness toyield 2-(6'-fluoro-2'-naphthyl)acrylic acid.

Similarly, other 2-(6'-substituted 2'-naphthyl)acrylic acids areprepared from the corresponding 6-substituted 2-naphthylacetic acidester derivatives.

EXAMPLE 6

A mixture of 24.4 g. of ethyl 6-methoxy-2-naphthylacetate, 2.4 g. ofsodium hydride, and 100 ml. of diethyl carbonate is stirred for fourhours at 20° C. The product, diethyl 6-methoxy-2-naphthylmalonate(isolated by acidification with dilute hydrochloric acid followed bymethylene chloride extraction), is added to 125 ml. of1,2-dimethoxyethane containing 33 g. of potassium tert-butoxide; themixture is allowed to stand for four hours at 60° C withchlorodifluoromethane being continually bubbled in after the mixture isinitially saturated. The mixture is carefully neutralized by addingaqueous oxalic acid; the product, diethyl2-(6'-methoxy-2'-naphthyl)-2-difluoromethylmalonate is isolated bymethylene chloride extraction and hydrolyzed by refluxing in 250 ml. ofmethanol containing 5 g. of potassium hydroxide and 5 ml. of water. Thecooled mixture is acidified with oxalic acid, and the product,2-(6'-methoxy-2'-naphthyl)-2-difluoromethylmalonic acid, is extractedwith methylene chloride. The dried product is decarboxylated by heatingto 180° C for six hours to give2-(6'-methoxy-2'-naphthyl)-3,3-difluoropropionic acid.

Similarly, the following 3,3-difluropropionic acid derivatives areprepared from the corresponding acetic acid esters, e.g.2-(6'-methyl-2'-naphthyl)-3,3-difluoropropionic acid,2-(6'-isopropyl-2'-naphthyl)-3,3-difluoropropionic acid,2-(6'-cyclopropyl-2'-naphthyl)-3,3-difluoropropionic acid,2-(6'-trifluoromethyl-2'-naphthyl)-3,3-difluoropropionic acid,2-(6'-methylthio-2'-naphthyl)-3,3,-difluoropropionic acid, etc.

EXAMPLE 7

A mixture of 31.6 g. of diethyl 6-methoxy-2-naphthylmalonate, 2.4 g. ofsodium hydride, and 350 ml. of methanol is stirred for one hour; then 24g. of methyl iodide are added and the resulting mixture is refluxed fortwo hours. The cooled mixture is neutralized with aqueous oxalic acid.The product, diethyl 2-(6'-methoxy-2'-naphthyl)-2-methylmalonate, isisolated, hydrolyzed, and decarboxylated as described in Example 6 togive 2-(6'-methoxy-2'-naphthyl)propionic acid.

EXAMPLE 8

A mixture of 26 g. of methyl 2-(6'-methylthio-2'-naphthyl)propionate,200 ml. of glacial acetic acid, and 2 ml. of a 48 percent hydrobromicacid are refluxed for two hours. The mixture is diluted with one literof water and extracted with methyl chloride. The extracts are combined,washed with water, dried over sodium sulfate, filtered, and evaporatedto yield 2-(6'-thio-2'-naphthyl)propionic acid. The latter compound isadded to a mixture of 150 ml. of dioxane and 150 ml. of aqueous 20percent sodium hydroxide. The resulting mixture is heated to 65° C andsaturated with chlorodifluoromethane. The resulting mixture is allowedto stand for two hours while continuously bubbling inchlorodifluoromethane. The cooled reaction mixture is then acidified bythe addition of aqueous 1 N hydrochloric acid and extracted with diethylether. The extracts are combined, washed with water to neutrality, driedover sodium sulfate, filterd, and evaporated to yield2-(6'-difluoromethylthio-2'-naphthyl)propionic acid.

Repeating this procedure with methyl2-(6'-methoxy-2'-naphthyl)propionate yields2-(6'-difluoromethoxy-2'-naphthyl)propionic acid.

EXAMPLE 9

A mixture of 23 g. of methyl 2-(6'-hydroxy-2'-naphthyl)propionate, 25 g.of chlorodimethyl ether, and 500 ml. of dimethylformamide is allowed tostand at room temperature for 12 hours. The reaction mixture isevaporated under reduced pressure to give methyl2-(6'-methoxymethyloxy-2'-naphthyl)propionate.

The methyl 2-(6'-hydroxy-2'-naphthyl)propionate is prepared by refluxingmethyl 2-(6'-methoxy-2'-napthyl)propionate with boron tribromide ismethylene chloride, hydrolyzing the resulting 6'-orthoboric ester withaqueous alkali to give 2-(6'-hydroxy-2'-naphthyl)propionic acid, andthen reesterifying the methanol and acid.

Methyl 2-(6'-isopropoxymethyloxy-2'-naphthyl)propionate, methyl2-(6'-ethoxymethyloxy-2'-naphthyl)propionate, and methyl2-(6'-methylthiomethyloxy-2'-naphthyl)propionate are similarly preparedby utilizing chloromethyl isopropyl ether, chloromethyl ethyl ether, andmethylthio chloromethane, respectively, in place of chlorodimethyl etherin the above process.

Methyl 2-(6'-methoxymethylthio-2'-naphthyl)propionate is prepared byutilizing methyl 2-(6'-thio-2'-naphthyl)propionate in the above process.Likewise, methyl 2-(6'-methylthiomeththio-2'-naphthyl)propionate isprepared by using methyl 2-(6'-thio-2'-naphthyl)-propionate andmethylthio chloromethane in the process described.

EXAMPLE 10

Chlorine gas is bubbled through a mixture of 23 g. of methyl2-(6'-methyl-2'-naphthyl)propionate and 1 g. of phosphorus pentachloridein 200 ml.of carbon tetrachloride in the presence of light until 21.3 g.of chlorine have been taken up. The reaction mixture is diluted with 200ml. of pyridine, filtered, further diluted with 500 ml. of ether, washedwith water to neutrality, dried over sodium sulfate, and evaporated toyield methyl 2-(6'-trichloromethyl-2'-naphthyl)propionate. The aboveproduct is then refluxed in a mixture of 500 ml. of chlorobenzene and17.9 g. of antimony trifluoride. The cooled reaction mixture is washedwith water, dried over sodium sulfate, and evaporated to yield methyl2-(6'-trifluoromethyl-2'-naphthyl)propionate.

EXAMPLE 11

A solution of 0.64 g. of 2-(6'-iodo-2'-naphthyl)propionic acid in 5 ml.of thionyl chloride and 10 ml. of benzene is refluxed for 1 hour andthen evaporated to dryness under vacuum. The resulting acid chloride isthen dissolved in 10 ml. of ether and added to a solution of 2 ml. ofdiethylamine in 20 ml. of ether. After washing with water, the ethersolution is evaporated, and the residue crystallized from acetone givingN,N-diethyl-2-(6'-iodo-2'-naphthyl)propionamide.

100 Mg. of the amide, 200 mg. of copper powder, 1 ml. ofdimethylformamide and 0.5 ml. of trifluoromethyl iodide in a sealedglass tube are heated to 135° C for 3 hours. The products are extractedinto hexane which is washed with water. Evaporation of the solvent givesN,N-diethyl-2-(6'-trifluoromethyl-2'-naphthyl)propionamide. The latteramide in 5 ml. of acetic acid and 5 ml. of concentrated hydrochloricacid is heated under reflux for 10 days. The mixture is then evaporatedto dryness, and the residue distributed between sodium bicarbonatesolution and ether. Acidification of the aqueous layer, and etherextraction gives 2-(6'-trifluoromethyl-2'-naphthyl)propionic acid whichis recrystallized from acetone-hexane.

EXAMPLE 12

A mixture of 24.2 g. of methyl 2-(6'-ethyl-2'-naphthyl)propionate 17.8g. of N-bromosuccinimide, and 10 mg. of benzoyl peroxide, and 300 ml. ofchloroform are refluxed for two hours in the presence of light. Themixture is filtered and evaporated. The residue is heated to 200 ml. ofglacial acetic acid containing 16. g. of sodium acetate at 60° C for 24hours. Five hundred milliliters of water are added to the resultingmixture and the product is extracted by diethyl ether extractions. Theproduct, methyl 2-[6'-(1"-acetoxyethyl)-2'-naphthyl]propionate, ishydrolyzed by adding it to a 5 percent aqueous sodium carbonatesolution. The product, 2-(6'-(1"-hydroxyethyl)-2'-naphthyl)propionicacid is isolated by acidification and diethyl ether extractions. Theisolated product is isolated by adding it to 200 ml. of glacial aceticacid containing 25 g. of chromium trioxide. The resulting mixture isallowed to stand at room temperature for one hour. Two hundredmilliliters of a 10 percent sodium bisulfite solution are added and themixture is extracted with diethyl ether. The extracts are combined,washed with water to neutrality, dried over sodium sulfate, filtered,and evaporated to give 2-(6'-acetyl-2'-naphthyl)propionic acid. To amixture of 24 g. of a 2-(6'-acetyl-2'-naphthyl)propionic acid and 200ml. of diethyl ether are added 4.2 g. of diazomethane in 100 ml. ofdiethyl ether. The resulting mixture is evaporated to give methyl2-(6'-acetyl-2'-naphthyl)propionate. The product is added to 200 ml. ofaqueous 20 percent sodium hypochlorite. The resulting mixture is allowedto stand for four hours at room temperature. The mixture is acidified bythe addition of aqueous 1 N hydrochloric acid and extracted with diethylether. The extracts are combined, washed with water to neutrality, driedover sodium sulfate, filtered, and evaporated to give2-(6'-carboxy-2'-naphthyl)propionic acid.

The latter compound is esterified with 8.4 g. of diazomethane indiethylether, as described above to give methyl2-(6'-methoxycarbonyl-2'-naphthyl)propionate. The diester is hydrolyzedby refluxing in 200 ml. of ethyl alcohol containing 4 g. (one molarequivalent) of sodium hydroxide for five hours. The cooled mixture isacidified by the addition of aqeuous 1 N hydrochloric acid and theproduct is isolated by methylene chloride extraction to give2-(6'-methoxycarbonyl-2'-naphthyl)propionic acid.

A mixture of 25.8 g. of 2-(6'-methoxycarbonyl-2'-naphthyl)propionicacid, 4 g. of sodium hydroxide, 10 ml. of water, and 500 ml. of methanolare heated to 50° C, cooled and evaporated. The residue is taken up in500 ml. of diethylene glycol dimethyl ether and diborane is bubbledthrough for 18 hours. The reaction mixture is acidified by the additionof aqueous 1 N hydrochloric acid. The mixture is extracted withmethylene chloride. The extracts are combined, washed with water toneutrality, dried over sodium sulfate, filtered, and evaporated to give2-(6'-hydroxymethyl-2'-naphthyl)propionic acid.

To a mixture of 24.4 g. of methyl2-(6'-hydroxymethyl-2'-naphthyl)propionate [prepared from2-(6'-hydroxymethyl-2'-naphthyl)propionic acid by esterifying the latterwith diazomethane in ethanol as described above] and 500 ml. of benzeneare added 2.4 g. of sodium hydride. The resulting mixture is stirred fortwo hours; then 12.2 g. of methyl iodide are added. The resultingmixture is neutralized by the addition of aqueous 1 N hydrochloric acidafter it has been allowed to stand for one hour; the mixture is thenwashed with water, dried over sodium sulfate, and evaporated to givemethyl 2-(6'-methoxymethyl-2'-naphthyl)propionate.

Methyl 2-(6'-ethoxymethyl-2'-naphthyl)propionate is prepared by using13.7 g. of ethyl iodide in place of methyl iodide in the above process.

EXAMPLE 13

A mixture of 23 g. of 2-(6'-hydroxymethyl-2'-naphthyl)propionic acid,230 g. of manganese dioxide, and 2 l. of chloroform are stirred for 12hours; the mixture is filtered and evaporated to give2-(6'-formyl-2'-naphthyl)propionic acid.

A mixture of 22.8 g. of 2-(6'-formyl-2'-naphthyl)propionic acid, 14 g.of hydroxylamine hydrochloride, 25 g. of sodium acetate, and 1 l. ofethyl alcohol are refluxed for one hour; the cooled reaction is dilutedwith 1 l. of water and extracted with methylene chloride. The extractsare combined, washed with water to neutrality, dried over sodiumsulfate, filtered, and evaporated to give the oxime of2-(6'-formyl-2'-naphthyl)propionic acid. The above oxime is refluxed in1 l. of acetic anhydride containing 20 g. of p-toluenesulfonic acid forone hour; the reaction mixture is then evaporated to dryness. Theresidue is taken up in methylene chloride, washed with water, dried oversodium sulfate, filtered, and evaporated to yield2-(6'-cyano-2'-naphthyl)propionic acid.

Similarly, by means of the above processes,2-(6'-acetyl-2'-naphthyl)-3,3-difluoropropionic acid,2-(6'-carboxy-2'-naphthyl)-3,3-difluoropropionic acid,2-(6'-methoxycarbonyl-2'-naphthyl)-3,3-difluoropropionic acid,2-(6'-hydroxymethyl-2'-naphthyl)-3,3-difluoropropionic acid,2-(6'-formyl-2'-naphthyl)-3,3-difluoropropionic acid, and the oximethereof, and 2-(6'-cyano-2'-naphthyl)-3,3-difluoropropionic acid areprepared from methyl 2-(6'-ethyl-2'-naphthyl)-3,3-difluoropropionate.

EXAMPLE 14

To a mixture of 20 g. of sodium hydroxide and 400 ml. of methanol areadded 24.5 g. of methyl 2-(6'-methoxy-2'-naphthyl)propionate. Theresulting reaction mixture is heated to 60° C for five hours. The cooledmixture is acidified with aqueous 1 N hydrochloric acid and extractedwith methylene chloride. The extracts are combined, washed with water toneutrality, dried over sodium sulfate, filtered, and evaporated to give2-(6'-methoxy-2'-naphthyl)propionic acid.

Similarly, the other ester derivatives prepared by means of theprocedures described in the other examples herein are hydrolyzed to thecorresponding carboxylic acids.

EXAMPLE 15

A mixture of 2.3 g. of 2-(6'-methoxy-2'-naphthyl)propionic acid, 2.9 g.of cinchonidine, and 50 ml of methanol is stirred for two hours; themixture is then allowed to stand until crystallization is complete. Thecrystals are filtered off and washed with methanol. The crystals arerecrystallized from methanol, fitered, washed, and dried. The purecrystals are added to 60 ml. of 0.2 N hydrochloric acid. The resultingmixture is stirred for two hours and then extracted with diethyl ether.The extracts are combined, washed with water to neutrality, dried oversodium sulfate, and evaporated to yield d2-(6'-methoxy-2'-naphthyl)propionic acid. The filtrates from the aboveare acidified with aqueous dilute hydrochloric acid and the product isisolated by diethyl ether extractions to give 12-(6'-methoxy-2'-naphthyl)propionic acid.

Similarly, the optical isomers of the other α-monosubstituted2-naphthylacetic acid derivatives made by the procedures describedherein as separated.

EXAMPLE 16

A solution of 50:50 d and 1 2-(6'-methoxy-2'-naphthyl)propionic acid inmethanol is prepared by dissolving 230 g. of the racemic mixture in 4.6l. of warm methanol. The resulting solution is boiled until it becomesturbid; then sufficient methanol is added to make the solution clearagain. This hot solution is added to a solution of 296 g.of cinchonidinein 7.4 l. of methanol heated to about 60° C. The solutions are combinedwhile stirring, and the combined mixture is then allowed to obtain roomtemperature over a two hour period. After the reaction mixture hasobtained room temperature, it is stirred for an additional two hours andthen filtered. The filtered salt is washed with several portions of icecold methanol. The resulting washed salt is then dried under vacuum.

A saturated solution of the above salt in methanol is prepared byintially dissolving 100 g. of the above salt in 4 l. of methanol heatedto about 60° C. The mixture is then refluxed, and additional salt isadded until the solution becomes turbid; at this point, methanol isadded to make the solution clear again. The resulting mixture is allowedto cool to room temperature. After the cooled mixture is allowed tostand for two hours, it is filtered. The filtered salt is washed toyield the cinchonidine salt of d 2-(6'-methoxy-2'-naphthyl)propionicacid.

The above recrystallization is repeated 9 times using 2.5 of methanol inplace of 4 to yield the cinchonidine salt of d2-(6'-methoxy-2'-naphthyl)propionic acid.

The filtrates from the above procedures are combined and evaporated. Theresulting salt is added to 1500 ml. of hot ethanol; the hot mixture isslowly allowed to cool to 0° C over 12 hours, then the cooled mixture isfiltered. The filtered salt crystals are washed 5 times with ice coldethanol. The salt is then recrystallized an additional 4 times, firstfrom 1350 ml. of ethanol:water (26:1), secondly from 1150 ml. ofethanol:water (55:2), thirdly from 900 ml. of ethanol:water (27:1) andlastly from 675 ml. of ethanol:water (26:1) to yield the salt ofcinchonidine and l 2-(6'-methoxy-2'-naphthyl)propionic acid.

One hundred grams of the cinchonidine salt of l2-(6'-methoxy-2'-naphthyl)propionic acid is added to a stirred mixtureof 600 ml. of ethyl acetate and 450 ml. of 2 N aqueous hydrochloricacid. After the mixture has been stirred for two hours, the ethylacetate layer is removed and washed with water to neutrality, dried oversodium sulfate, and evaporated to yield l2-(6'-methoxy-2'-naphthyl)propionic acid.

Similarly, d 2-(6'-methoxy-2'-naphthyl)propionic acid is prepared fromthe cinchonidine salt of d 2-(6'-methoxy-2'-naphthyl)-propionic acid.

The racemate of other 2-(6'-substituted-2'-naphthyl)propionic acidderivatives made by the procedures described herein are resolved bymeans of the above procedure. For example, d2-(6'-methyl-2'-naphthyl)propionic acid and l2-(6'-methyl-2'-naphthyl)propionic acid, d2-(6'-methylthio-2'-naphthyl)propionic acid and l2-(6'-methylthio-2'-naphthyl)propionic acid,d2-(6'-difluoromethoxy-2'-naphthyl)propionic acid and l2-(6'-difluoromethoxy-2'-naphthyl)propionic acid, and d2-(6'-methylthio-2'-naphthyl)-3,3-difluoropropionic acid and l2-(6'-methylthio-2'-naphthyl)-3,3-difluoropropionic acid can be resolvedfrom racemic mixtures of the corresponding2-(6'-methyl-2'-naphthyl)propionic acid,2-(6'-methylthio-2'-naphthyl)propionic acid,2-(6'-difluoromethoxy-2'-naphthyl)propionic acid and2-(6'-methylthio-2'-naphthyl)-3,3-difluoropropionic acid by means of theabove described process.

EXAMPLE 17

To a mixture of 4 g. of sodium hydroxide and 500 ml. of methanol areadded 24.6 g. of 2-(6'-methylthio-2'-naphthyl)propionic acid. Themixture is stirred for 1 hour at 50° C. The cooled mixture is thenevaporated to give the sodium salt of2-(6'-methylthio-2'-naphthyl)propionic acid.

By employing potassium hydroxide, diethylamine, lysine, caffeine, orprocaine in place of sodium hydroxide in the above process, thepotassium, triethylamine, lysine, caffeine, or procaine salt of2-(6'-methylthio-2'-naphthyl)propionic acid is obtained.

By means of the above procedure, the addition salts of2-(6'-substituted-2'-naphthyl)acetic acid derivatives prepared inExamples 1-16 can be prepared.

EXAMPLE 18

To a mixture of 4 g. of sodium hydroxide and 500 ml. of aqueousmethanol, there is added 23 g. of d 2-(6'-methoxy-2'-naphthyl)propionicacid. The mixture is stirred for three hours at room temperature; themixture is then evaporated to give sodium d2-(6'-methoxy-2'-naphthyl)propionate.

By employing 5.6 g. of potassium hydroxide in place of sodium hydroxidein the above procedure, potassium d 2-(6'-methoxy-2'-naphthyl)propionateis obtained. By employing 3.71 g. of calcium hydroxide in place ofsodium hydroxide in the above process, calcium di[d2-(6'-methoxy-2'-naphthyl)-propionate] is obtained.

Similarly, the sodium, potassium and calcium salts of the2-(6'-substituted-2'-naphthyl)acetic acid derivatives of Examples 1-16are prepared by means of the above process. For example

sodium l 2-(6'-methoxy-2'-naphthyl)propionate,

sodium d and l 2-(6'-methyl-2'-naphthyl)propionate,

sodium d and l 2-(6'-trifluoromethyl-2'-naphthyl)propionate,

sodium d and l 2-(6'-methoxy-2'-naphthyl)propionate,

sodium d and l 2-(6'-difluoromethoxy-2'-naphthyl)propionate,

sodium d and l 2-(6'-chloro-2'-naphthyl)propionate,

sodium d and l 2-(6'-methylthio-2'-naphthyl)propionate,

sodium d and l 2-(6'-difluoromethylthio-2'-naphthyl)propionate,

sodium d and l 2-(6'-vinyl-2'-naphthyl)propionate,

sodium d and l 2-(6'-ethyl-2'-naphthyl)-3,3-difluoropropionate,

sodium d and l 2-(6'-cyclopropyl-2'-naphthyl)-3,3-difluoropropionate,

sodium d and l 2-(6'-fluoro-2'-naphthyl)-3,3-difluoropropionate,

sodium d and l 2-(6'-methoxy-2'-naphthyl)-3,3-difluoropropionate,

sodium d and l2-(6'-difluoromethoxy-2'-naphthyl)-3,3-difluoropropionate,

sodium d and l 2-(6'-methylthio-2'-naphthyl)-3,3-difluoropropionate.

sodium d and l 2-(6'-methyl-2'-naphthyl)-3,3-difluoropropionate,

sodium d and l 2-(6'-isopropyl-2'-naphthyl)-3,3-difluoropropionate,

sodium d and l 2-(6'-chloro-2'-naphthyl)-3,3-difluoropropionate,

sodium d and l 2-(6'-vinyl-2'-naphthyl)-3,3-difluoropropionate,

sodium d and l2-(6'-trifluoromethyl-2'-naphthyl)-3,3-difluoropropionate,

sodium d and l 2-(6'-acetyl-2'-naphthyl)-3,3-difluoropropionate, and

sodium d and l 2-(6'-ethynyl-2'-naphthyl)-3,3-difluoropropionate, areprepared from the corresponding 2-(6'-substituted-2'-naphthyl)-propionicacid derivatives by means of the above process.

EXAMPLE 19

To a mixture of 5.55 g. of calcium chloride and 300 ml. of water, thereis added a solution of 25.2 g. of sodium d2-(6'-methoxy-2'-naphthyl)propionate and 300 ml. of water; the resultingmixture is allowed to stand for 12 hours at room temperature. Themixture is then filtered, and the filtered salt is washed with severalportions of ice cold water. The washed salt is dried under vacuum toyield the calcium d 2-(6'methoxy-2'-naphthyl)propionate.

By employing 4.77 g. of magnesium chloride in the above process, themagnesium d 2-(6'-methoxy-2'-naphthyl)propionate is obtained.

By means of the above process, the calcium and magnesium salts of the2-(6'-substituted-2'-naphthyl)acetic acid derivatives of Examples 1-16are prepared after initially preparing the sodium or potassium salts bymeans of the process described in Example 18. For example,

the calcium salt of 2-(6'-methyl-2'-naphthyl)propionic acid,

the calcium salt of 2-(6'-ethyl-2'-naphthyl)propionic acid,

the calcium salt of 2-(6'-trifluoromethyl-2'-naphthyl)propionic acid,

the calcium salt of 2-(6'-methoxy-2'-naphthyl)propionic acid,

the calcium salt of 2-(6'-difluoromethoxy-2'-naphthyl)propionic acid.

the calcium salt of 2-(6'-chloro-2'-naphthyl)propionic acid,

the calcium salt of 2-(6'-fluoro-2'-naphthyl)propionic acid,

the calcium salt of 2-(6'-methylthio-2'-naphthyl)propionic acid,

the calcium salt of 2-(6'-difluoromethylthio-2'-naphthyl)propionic acid,

the calcium salt of 2-(6'-methyl-2'-naphthyl)-3,3-difluoropropionicacid,

the calcium salt of2-(6'-trifluoromethyl-2'-naphthyl)-3,3-difluoropropionic acid,

the calcium salt of 2-(6'-chloro-2'-naphthyl)-3,3-difluoropropionicacid,

the calcium salt of l 2-(6'-methoxy-2'-naphthyl)-3,3-difluoropropionicacid,

the calcium salt of 2-(6'-methoxy-2'-naphthyl)-3,3-difluoropropionicacid,

the calcium salt of2-(6'-difluoromethylthio-2'-naphthyl)-3,3-difluoropropionic acid,

the calcium salt of 2-(6'-ethynyl-2'-naphthyl)-3,3-difluoropropionicacid,

the calcium salt of 2-(6'-methyl-2'-naphthyl)-3,3-difluoropropionicacid, and the calcium salt of2-(6'-methylthio-2'-naphthyl)-3,3-difluoropropionic acid are preparedfrom the corresponding sodium or potassium2-(6'-substituted-2'-naphthyl)propionate derivatives (prepared by theprocess described in Example 18 ) by means of the above process.

EXAMPLE 20

Repeating the procedure of Example 19 but replacing calcium chloridewith ferrous chloride, zinc chloride, manganous chloride, ferricchloride or manganic chloride yields the respective ferrous, zincmanganous, ferric, manganic 2-(6'-substituted-2'-naphthyl) propionates,i.e.

ferrous d 2-(6'-methoxy-2'-naphthyl)propionate,

zinc d 2-(6'-methoxy-2'naphthyl)propionate,

manganous d 2-(6'-methoxy-2'-naphthyl)propionate,

ferric d 2-(6'-methoxy-2'-naphthyl)propionate, and

manganic d 2-(6'-methoxy-2'naphthyl)propionate.

EXAMPLE 21

To a mixture of 16.2 g of aluminum triethoxide and 1 l of benzene, thereare added 69 g. of d 2-(6'-methoxy-2'-naphthyl)propionic acid. Theresulting mixture is refluxed for 24 hours; the mixture is then cooledand evaporated under reduced pressure to give the aluminum salt of d2-(6'-methoxy-2'-naphthyl)propionic acid.

By means of the above procedure, the aluminum salts of the2-(6'-substituted-2'-naphthyl)acetic acid derivatives of Examples 1-16can be prepared. For example,

the aluminum salt of 2-(6'-methyl-2'-naphthyl)propionic acid,

the aluminum salt of 2-(6'-difluoromethoxy-2'-naphthyl)propionic acid,

the aluminum salt of 2-(6'-fluoro-2'-naphthyl)propionic acid,

the aluminum salt of 2-(6'-ethynyl-2'-naphthyl)propionic acid,

the aluminum salt of 2-(6'-isopropyl-2'-naphthyl)-3,3-difluoropropionicacid,

the aluminum salt of l 2-(6'-methoxy-2'-naphthyl)propionic acid,

the aluminum salt of 2-(6'-methoxy-2'naphthyl)-3,3-difluoropropionicacid,

the aluminum salt of 2-(6'-chloro-2'-naphthyl)-3,3-difluoropropionicacid,

the aluminum salt of 2-(6'-methylthio-2'-naphthyl-3,3-difluoropropionicacid, and

the aluminum salt of 2-(6'-acetyl-2'-naphthyl)-3,3-difluoropropionicacid are prepared from the corresponding 2-(6'-substituted-2'-naphthyl)propionic acid derivatives by means of the above described process.

EXAMPLE 22

To a mixture of 50 ml. of concentrated aqueous ammonia in 500 ml. ofmethanol, there are added 23 g. of d 2-(6'-methoxy-2'-naphthyl)propionicacid. The resulting mixture is stirred for two hours and is thenevaporated to dryness to yield the ammonium salt of d2-(6'-methoxy-2'-naphthyl)propionate.

By employing trimethylamine, triethylamine or tripropylamine in place ofammonia in the above process, trimethylammonium d2-(6'-methoxy-2'-naphthyl)propionate, triethylammonium d2-(6'-methoxy-2'-naphthyl)propionate, and tripropylammonium d2-(6'-methoxy-2'-naphthyl)propionate, respectively, are obtained. Bymeans of the above process the ammonia, trimethylamine, triethylamineand tripropylamine salts of the 2-(6'-substituted-2'-naphthyl)aceticacid derivatives of Examples 1-16 can be prepared. For example

ammonium l 2-(6'-methoxy-2'-naphthyl)propionate,

ammonium 2-(6'-methyl-2'-naphthyl)propionate,

ammonium 2-(6'-acetyl-2'-naphthyl)propionate,

ammonium 2-(6'-isopropyl-2'-naphthyl)propionate,

ammonium 2-(6'-trifluoromethyl-2'-naphthyl)propionate,

ammonium 2-(6'-chloro-2'-naphthyl)propionate,

ammonium 2-(6'-methylthio-2'-naphthyl)propionate,

ammonium 2-(6'-methyl-2'-naphthyl)-3,3-difluoropropionate,

ammonium 2-(6'-fluoro-2'-naphthyl)-3,3-difluoropropionate,

ammonium 2-(6'-difluoromethoxy-2'naphthyl)-3,3-difluoropropionate,

ammonium 2-(6'-methoxy-2'-naphthyl)-3,3-difluoropropionate, and

ammonium 2-(6'-vinyl-2'-naphthyl)-3,3-difluoropropionate are preparedfrom the corresponding 2-(6'-substituted-2'-naphthyl)propionic acidderivatives.

EXAMPLE 23

To a mixture of 27.3 g. of procaine and 500 ml. of aqueous methanol,there are added 23 g. of d 2-(6'-methoxy-2'-naphthyl)propionic acid; theresulting mixture is stirred for 16 hours at room temperature. Themixture is then evaporated under reduced pressure to give the procainesalt of 2-(6'-methoxy-2'-naphthyl)propionic acid.

In a similar manner, by employing 14.6 g. of lysine, 17.4 g. of arginineor 19.4 g. of caffeine in place of procaine in the above process, thelysine, arginine or caffeine salt of d2-(6'-methoxy-2'-naphthyl)propionic acid is respectively, obtained.

Similarly, the lysine, caffeine, arginine and procaine salts of the2-(6'-substituted-2'-naphthyl)acetic acid derivatives of Examples 1-16can be prepared. For example,

the procaine salt of 2-(6'-cyclopropyl-2'-naphthyl)propionic acid,

the procaine salt of 2-(6'-fluoro-2'naphthyl)propionic acid,

the procaine salt of 2-(6'-difluoromethylthio-2'-naphthyl)propionicacid,

the procaine salt of 2-(6'-isopropyl-2'naphthyl)-3,3-difluoropropionicacid,

the procaine salt of l 2-(6'-methoxy-2'-naphthyl)propionic acid,

the procaine salt of2-(6'-trifluoromethyl-2'-naphthyl-3,3-difluoropropionic acid,

the procaine salt of 2-(6'-methyl-2'-naphthyl)propionic acid,

the procaine salt of 2-(6'-chloro-2'-naphthyl)-3,3-difluoropropionicacid,

the procaine salt of 2-(6'-methoxy-2'-naphthyl)-3,3-difluoropropionicacid,

the procaine salt of2-(6'-difluoromethoxy-2'-naphthyl)-3,3-difluoropropionic acid,

the procaine salt of 2-(6'-methyl-2'-naphthyl)-3,3-difluoropropionicacid, and

the procaine salt of2-(6'-difluoromethylthio-2'-naphthyl)-3,3-difluoropropionic acid areprepared from the corresponding 2-(6'substituted-2'-naphthyl)propionicacid derivatives.

EXAMPLE 24

The ethanolamine salt of d 2-(6'-methoxy-2'-naphthyl)propionic acid isprepared from d 2-(6'-methoxy-2'naphthyl)propionic acid by means of theprocess described in Examples 23, except 6.1 g. of ethanolamine is usedin place of procaine.

In a similar manner, the ethanolamine salts of the2-(6'-substituted-2'-naphthyl) acetic acid derivatives of Examples 1-16are prepared.

EXAMPLE 25

The 2-(diethylamino)ethanol salt of d2-(6'-methoxy-2'-naphthyl)propionic acid is prepared from d2-(6'-methoxy-2'-naphthyl)propionic acid by means of the processdescribed in Example 23, except 11.8 g. of 2-(diethylamino)ethanol isused in place of procaine.

In a similar manner, the 2-(diethylamino)ethanol salts of the2-(6'-substituted-2'-naphthyl)acetic acid derivatives of Examples 1-16are prepared.

EXAMPLE 26

The 2-(dimethylamino)ethanol salt of d2-(6'-methoxy-2'-naphthyl)propionic acid is prepared from d2-(6'-methoxy-2'-naphthyl)propionic acid by means of the processdescribed in Example 23 except 9.0 g. of 2-(dimethylamino)ethanol isused in place of procaine.

In a similar manner, the 2-(dimethylamino)ethanol salts of the2-(6'-substituted-2'-naphthyl)acetic acid derivatives of Examples 1-16are prepared.

EXAMPLE 27

The methyl glucamine salt of d 2-(6'-methoxy-2'-naphthyl)propionic acidis prepared from d 2-(6'-methoxy-2'naphthyl) propionic acid by means ofthe process described in Example 23 except 19.5 g. of methyl glucamineis used in place of procaine.

In a similar manner, the methyl glucamine salts of the2-(6'-substituted-2'-naphthyl)acetic acid derivatives of Examples 1-16are prepared.

EXAMPLE 28

The ethylenediamine salt of d 2-(6'-methoxy-2'-naphthyl)propionic acidis prepared from d 2-(6'-methoxy-2'-naphthyl)propionic acid by means ofthe process described in Example 23, except, 6.0 g of ethylenediamine isused in place of procaine.

In a similar manner, the ethylenediamine salts of the2-(6'-substituted-2'-naphthyl)acetic acid derivatives of Examples 1-16are prepared.

EXAMPLE 29

At room temperature, boron trifluoride etherate is added to a mixture of23 g. of d 2-(6'-methoxy-2'-naphthyl)propionic acid in 100 ml. ofisoamyl alcohol for a period of 24 hours. The mixture is then dilutedwith 250 ml. of water and extracted with several portions of methylenechloride. The extracts are combined, washed with water to neutrality,dried over sodium sulfate and evaporated under reduced pressure to yieldd isoamyl 2-(6'-methoxy-2'-naphthyl)propionate.

Similarly, by means of the above described process, 1 isoamyl2-(6'-methoxy-2'-naphthyl)propionate is prepared from l2-(6'-methoxy-2'-naphthyl)propionic acid.

In a similar manner, the 2-(6'-substituted-2'-naphthyl)acetic acidderivatives prepared in Examples 1-16 are esterified by means of theabove process to prepare the corresponding isoamyl2-(6'substituted-2'-naphthyl)acetate derivatives. For example,

isoamyl 2-(6'-methoxy-2'-naphthyl)acetate,

d and l isoamyl 2-(6'-methoxy-2'-naphthyl)propionate,

d and l isoamyl 2-(6'-methoxy-2'-naphthyl)-3,3-difluoropropionate,

d and l isoamyl 2-(6'-methoxy-2'-naphthyl)acrylate,

isoamyl 2-(6'-isopropyl-2'-naphthyl)acetate,

d and l isoamyl 2-(6'-isopropyl-2'-naphthyl)propionate,

d and l isoamyl 2-(6'-isopropyl-2'-naphthyl)-3,3-difluoropropionate,

d and 1 isoamyl 2-(6'-isopropyl-2'-naphthyl)acrylate,

isoamyl 2-(6'-ethynyl-2'-naphthyl)acetate,

d and l isoamyl 2-(6'-ethynyl-2'-naphthyl)propionate,

d and l isoamyl 2-(6'-ethynyl-2'-naphthyl)-3,3-difluoropropionate,

d and l isoamyl 2-(6'-ethynyl-2'-naphthyl)acrylate,

isoamyl 2-(6'-difluoromethylthio-2'-naphthyl)acetate,

d and l isoamyl 2-(6'-difluoromethylthio-2'-naphthyl)-propionate,

d and l isoamyl2-(6'-difluoromethylthio-2'-naphthyl)-3,3-difluoropropionate, and

d and l isoamyl 2-(6'-difluoromethylthio-2'-naphthyl)acrylate areprepared from the corresponding 2-(6'-substituted-2'-naphthyl)aceticacid derivatives.

EXAMPLE 30

A mixture of 246 g. of d 2-(6'-methoxy-2'-naphthyl)propionic acid and1.5 l. of benzene is treated with 144 g. of thionyl chloride at roomtemperature until the evolution of gas ceases. The mixture is cooled andevaporated to dryness under high vacuum to yield the acid chloride of2-(6'-methoxy-2'-naphthyl)propionic acid.

The above acid chloride in 500 ml. of benzene is added dropwise to amixture of one liter of pyridine and 500 g. of palmityl alcohol whilestirring and maintaining the reaction mixture at about room temperature.After the addition of the acid chloride product, the reaction mixture isheated to 90° for 5 hours and then cooled to room temperature. Thereaction mixture is then diluted with one liter of water; then theorganic layer is drawn off. The organic extract is washed with water toneutrality, dried over sodium sulfate and evaporated to dryness underreduced pressure to yield d palmityl2-(6'-methoxy-2'-naphthyl)propionate. The ester is further purified bychromatographing on acid grade alumina eluting with hexane:diethyl ether(6:1).

Similarly, l palmityl 2-(6'-methoxy-2'-naphthyl)propionate is preparedfrom l 2-(6'-methoxy-2'-naphthyl)propionic acid by means of the abovedescribed process.

In a similar manner the 2-(6'-substituted-2'-naphthyl)acetic acidderivatives of Examples 1-16 are esterified by means of the aboveprocess to yield the corresponding palmityl2-(6'-substituted-2'-naphthyl)acetate derivatives. For example,

palmityl 2-(6'-methylthio-2'-naphthyl)acetate,

palmityl 2-(6'-methylthio-2'-naphthyl)propionate,

palmityl 2-(6'-methylthio-2'naphthyl)-3,3difluoropropionate,

palmityl 2-(6'-methylthio-2'-naphthyl)acrylate,

palmityl 2-(6'-vinyl-2'-naphthyl)acetate,

palmityl 2-(6'-vinyl-2'-naphthyl)propionate,

palmityl 2-(6'-vinyl-2'-naphthyl)-3,3-difluoropropionate, and

palmityl 2-(6'-vinyl-2'-naphthyl)acrylate are prepared from thecorresponding 2-(6'-substituted-2'-naphthyl)acetic acid derivatives bymeans of the above process.

EXAMPLE 31

At room temperature, anhydrous hydrogen chloride is bubbled through amixture of 520 g. of 2-(6'-trifluoromethyl-2'-naphthyl)propionic acid,2.5 liters of carbon tetrachloride and 2.5 liters of hexanol until themixture is saturated with hydrogen chloride. The resulting mixture isallowed to stand for 24 hours under anhydrous conditions, then themixture is diluted with 15 l. of water and extracted with chloroform.The extracts are combined, washed with water and aqueous sodiumbicarbonate, washed with water to neutrality, dried over sodium sulfate,and evaporated under reduced pressure to yield hexyl2-(6'-trifluoromethyl-2'-naphthyl)propionate.

By employing the 2-(6'-substituted-2'-naphthyl)acetic acid derivativesof Examples 1-16 in the above process, the corresponding hexyl2-(6'-substituted-2'-naphthyl)acetate derivatives are obtained. Forexample

hexyl 2-(6'-trifluoromethyl-2'-naphthyl)acetate,

hexyl 2-(6'trifluoromethyl-2'-naphthyl)-3,3difluoropropionate,

hexyl 2-(6'-trifluoromethyl-2'-naphthyl)acrylate,

hexyl 2-(6'ethyl-2'-naphthyl)acetate,

hexyl 2-(6'-ethyl-2'-naphthyl)propionate,

hexyl 2-(6'-ethyl-2'-naphthyl)-3,3-difluoropropionate,

hexyl 2-(6'-ethyl-2'-naphthyl)acrylate,

hexyl 2-(6'-ethynyl-2'-naphthyl)acetate,

hexyl 2-(6'-ethynyl-2'-naphthyl)propionate,

hexyl 2-(6'-ethynyl-2'-naphthyl)-3,3-difluoropropionate,

hexyl 2-(6'-ethynyl-2'-naphthyl)acrylate,

hexyl 2-(6'-acetyl-2'-naphthyl)acetate,

hexyl 2-(6'-acetyl-2'-naphthyl)propionate,

hexyl 2-(6'-acetyl-2'-naphthyl)-3,3-difluoropropionate, and

hexyl 2-(6'-acetyl-2'-naphthyl)acrylate are prepared from thecorresponding 2-(6'-substituted-2'-naphthyl)acetic acid derivatives.

EXAMPLE 32

A mixture of 21.4 g. of 2-(6'-methyl-2'-naphthyl)propionic acid, 1 ml.of dimethylformamide and 250 ml. of chloroform is refluxed with 12 g. ofthionyl chloride for 4 hours. The mixture is then cooled and evaporatedto dryness to yield 2-(6'-methyl-2'-naphthyl)propionyl chloride. Thelatter product is added to 250 ml. of carbon tetrachloride and 100 ml.of triethylamine. The resulting mixture is then treated with 50 ml. oftertiary butyl alcohol over a 1 hour period while maintaining thereaction temperature at 20° C. After the addition, the mixture isstirred for an additional 24 hours and diluted with 500 ml. of water.The aqueous mixture is extracted with methylene chloride; the extractsare combined, washed with water, dried over sodium sulfate andevaporated to yield tertiary butyl 2-(6'-methyl-2'-naphthyl)propionate.

EXAMPLE 33

Forty grams of powdered 2-(6'-chloro-2'-naphthyl)propionic acid aretreated with 14 g. of phosphorus trichloride dropwise at roomtemperature under anhydrous conditions. After the addition of thephosphorus trichloride, the reaction mixture is heated to 100° C for 4hours. The mixture is cooled, diluted with 200 ml. of carbontetrachloride, filtered and evaporated to yield2-(6'-chloro-2'-naphthyl)propionyl chloride.

The same product is obtained when 44.5 g. of the sodium salt of2-(6'-chloro-2'-naphthyl)propionic acid is used in place of2-(6'-chloro-2'-naphthyl)propionic acid and 15.3 g. of phosphorusoxychloride are used in place of phosphorus trichloride in the aboveprocess.

EXAMPLE 34

A mixture of 46 g. of 2-(6'-methyl-2'-naphthyl)propionic acid, 500 ml.of butanol, 600 ml. of tetrahydrofuran and 1 g. of p-toluenesulfonicacid are refluxed for 12 hours. The mixture is then cooled, diluted with10 l. of water, and extracted with diethyl ether. The extracts arecombined, washed with water and aqueous sodium bicarbonate, washed withwater to neutrality and dried over sodium sulfate and evaporated toyield butyl 2-(6'-methyl-2'-naphthyl)propionate.

The same result is obtained when 5 ml. of concentrated sulfuric acid isused in place of p-toluenesulfonic acid in the above process.

By employing the 2-(6'-substituted-2'-naphthyl)acetic acid derivativesof Examples 1-16 in the above process, the corresponding butyl2-(6'-substituted-2'-naphthyl)acetate derivatives are obtained. Forexample,

butyl 2-(6'-methyl-2'-naphthyl)acetate,

butyl 2-(6'-methyl-2'naphthyl)-3,3-difluoropropionate,

butyl 2-(6'-methyl-2'-naphthyl)acrylate,

butyl 2-(6'-difluoromethoxy-2'-naphthyl)acetate,

butyl 2-(6'-difluoromethoxy-2'-naphthyl)propionate,

butyl 2-(6'-difluoromethoxy-2'-naphthyl)-3,3-difluoropropionate,

butyl 2-(6'-difluoromethoxy-2'-naphthyl)acrylate,

butyl 2-(6'-chloro-2'-naphthyl)acetate,

butyl 2-(6'-chloro-2'-naphthyl)propionate,

butyl 2-(6'-chloro-2'-naphthyl)-3,3-difluoropropionate,

butyl 2-(6'-chloro-2'-naphthyl)acrylate,

butyl 2-(6'-methylthio-2'-naphthyl)acetate,

butyl 2-(6'-methylthio-2'-naphthyl)propionate,

butyl 2-(6'-methylthio-2'-naphthyl)-3,3-difluoropropionate, and

butyl 2-(6'-methylthio-2'-naphthyl)acrylate are prepred from thecorresponding 2-(6'-substituted-2'-naphthyl)acetic acid derivatives.

EXAMPLE 35

The following alcohol reagents are employed in place of tertiary butylalcohol in the process described in Example 32 to give the corresponding2-(6'-substituted-2'-naphthyl)acetic acid ester derivatives:2,3-dimethyl-2-hexanol, 2,5-dimethyl-2-hexanol, 2,3-dimethyl-3-pentanol,3-ethyl-3-pentanol, 2-methyl-2-heptanol, 3-methyl-3-heptanol,4-methyl-4-heptanol, 2-methyl-2-pentanol, 3-methyl-3-pentanol,2-methyl-2-octanol, 4-methyl-4-octanol and 2-methyl-2-nonanol.

In a similar manner, the 2-(6'-substituted-2'-naphthyl)acetic acidderivatives of Examples 1-16 can be esterified by means of the aboveprocess to yield the corresponding tertiary butyl2-(6'-substituted-2'-naphthyl)acetate derivatives.

EXAMPLE 36

The following alcohol reagents are employed in place of palmityl alcoholin Example 30 or in place of hexyl alcohol in Example 31 or in place ofbutyl alcohol in Example 32 to give the corresponding2-(6'-substituted-2'-naphthyl)acetic acid ester derivatives: methanol,ethanol, propanol, 2-propanol, butanol, 2-butanol, pentanol, 2-pentanol,3-pentanol, hexanol, 2-hexanol, 3-hexanol, heptanol, 2-heptanol,3-heptanol, 4-heptanol, octanol, 2-octanol, 4-octanol, nonanol,2-nonanol, 4-nonanol, 5-nonanol, decanol, 2-decanol, 3-decanol,4-decanol, 5-decanol, undecanol, dodecanol, 2-dodecanol, tridecanol,7-tridecanol, tetradecanol, pentadecanol, 2-pentadecanol, hexadecanol,heptadecanol, 2-heptadecanol, octadecanol, nonadecanol, 2-nonadecanol,eicosanol, heneicosanol, 2-methylpropanol, 3-methyl-2-butanol,3-methyl-2 -pentanol, 4-methyl-2-pentanol, 2-methyl-3-pentanol,3-methyl-2-hexanol, 2-methyl-3-hexanol, 3-methyl-3-hexanol,5-methyl-3-hexanol, 6-methyl-2-heptanol, 4-methyl-3-heptanol,5-methyl-3-heptanol, 2-methyl-3-octanol, 3-methyl-4-octanol,4-methyl-4-octanol, 2-methyl-3-nonanol, 2-methyl-4-nonanol,3-methyl-4-nonanol, 4-methyl-4-nonanol, 2-ethyl-1-butanol,4-ethyl-3-hexanol, 2-ethyl-1-hexanol, 5-ethyl-2-heptanol,3,3-dimethyl-1-butanol, 3,3-dimethyl-2-butanol, 2,3-dimethyl-1-butanol,2,2-dimethyl-3-butanol, 3,4-dimethyl-2-hexanol, 2,2-dimethyl-3-hexanol,2,5-dimethyl-3-hexanol, 2,2-dimethyl-3-heptanol, 2,4-dimethyl3-heptanol, benzyl alcohol, 2-phenylethanol, 3-phenylpropanol,2-tetradecanol, cyclonoanol, cyclobutanol, cyclodecanol,cycloheptanemethanol, cycloheptanol, cyclododecanol, cyclohexanol,2-cyclopentylethanol, 2-cyclohexylethanol, cyclohexylmethanol,cyclooctanemethanol, cyclooctanol, cyclopentylmethanol, cyclopentanol,3-cyclopentylpropanol, cyclopropylmethanol, 3-cyclohexylpropanol,cyclobutylmethanol, 2,3-dimethyl-2-butanol, 2,2-dimethyl-3-pentanol,2,3-dimethyl-1-pentanol, 2-hexadecanol, 2-methyl-1-butanol,3-methyl-1-butanol, 3-methyl-2-hexanol, 3-methyl-1-pentanol,4-methyl-1-pentanol, 2,2-dimethyl-1-propanol, 2-nonadecanol and thelike.

EXAMPLE 37

A solution of 85 g. of diazomethane in 3 liters of diethyl ether isslowly added to a solution of 460 g. of d2-(6'-methoxy-2'-naphthyl)propionic acid in 2 liters of diethyl etherover a one hour period with stirring. The resulting mixture is stirredfor an additional hour and then flushed with nitrogen gas until clear.The solution is then evaporated to yield the methyl ester of d2-(6'methoxy-2'-naphthyl)propionic acid.

By employing 112 g. of diazoethane in place of diazomethane in the aboveprocess, the ethyl ester of d 2-(6'-methoxy-2'-naphthyl)propionic acidis obtained.

EXAMPLE 38

The anti-inflammatory activity of the following2-(6'-substituted-2'naphthyl)propionic acid derivatives was comparedwith that of phenylbutazone by means of a carageenininduced rat pawinflammation test described by C.A. Winter et al., The Proceedings ofthe Society for Experimental Biology and Medicine, 111, 544-47, (1962).

The test was modified in that female rats weighing 80-90 grams wereemployed and the degree of inflammation was measured one hour after theinjection of carageenin in units of rear paw weight rather than rear pawvolume. The results are shown in the following table:

                  Table I                                                         ______________________________________                                                            Dose                                                                   No.    Range     Relative Potency                                             of     Tested    to phenylbutazone                               Compound Tested                                                                            Rats   Mg./rat   (phenylbutazone=1)                              ______________________________________                                        2,2-dimethylamine                                                                          89     0.033-2.7 5                                               salt of d 2-(6'-                                                              methoxy-2'-naphthyl)-                                                         propionic acid                                                                d 2-(6'-methoxy-                                                                           209    0.033-2.7 11                                              2'-naphthyl)pro-                                                              pionic acid                                                                   2-(6'-methylthio-                                                                          17     0.1-0.9   4                                               2'-naphthyl)pro-                                                              pionic acid                                                                   2-(6'-difluoro-                                                                            48     0.1-2.7   3                                               methoxy-2'-naphthyl)-                                                         propionic acid                                                                the calcium salt                                                                           110    0.036     10                                              of 2-(6'-methoxy-                                                             2'-naphthyl)pro-                                                              pionic acid                                                                   dl 2-(6'-chloro-                                                                           53     0.1-2.7   2                                               2'-naphthyl)pro-                                                              pionic acid                                                                   sodium salt of d                                                                           117    0.033-0.94                                                                              10                                              2-(6'-methoxy-2'-                                                             naphthyl)propionic                                                            acid                                                                          the 2-(dimethyl-                                                                           89     0.033-2.7 5                                               amino)ethanol salt                                                            of d 2-(6'-methoxy-                                                           2'-naphthyl)pro-                                                              pionic acid                                                                   ______________________________________                                    

EXAMPLE 39

The anti-pyretic activity of the following2-(6'-substituted-2'-naphthyl)propionic acid derivatives was compared tothe anti-pyretic activity of aspirin.

Anti-pyretic activity -- Female rats weighing 90-100 grams were used.The normal rectal temperature of the rats was recorded at hour 0,followed by the injection of 2 ml. of yeast suspension (the yeastsuspension is prepared by suspending one cake of Fleischman's yeast in22 ml. 0.9% NaCl) subcutaneously (1 ml. dorsally, 1 ml. ventrally). Theinjection sites are massaged to spread the suspension beneath the skin.The yeast injection induces elevated body temperature. At hour 17, therats were massaged again to stimulate a further increase in bodytemperature. (It was found that handling the rats at the time the secondtemperature was taken resulted in a rise in body temperature). At hour18, the second rectal temperature was recorded, after which the testmaterial was administered orally by gavage in 1 ml. aqueous vehicle.(The aqueous vehicle consists of 0.9% NaCl, 0.4% polysorbate 80, 0.5%carboxymethyl cellulose, 0.9% benzyl alcohol and water.) The thirdrectal temperature was obtained two hours after administration of thetest material.

The degree of anti-pyretic activity was measured as a reduction intemperature (F°) from the second to the third temperature readings(temperature at hour 18 - temperature at hour 20) with respect to acontrol. The results are shown in the following table:

                  Table II                                                        ______________________________________                                                              Dose                                                                   No.    Range     Relative Potency                                             of     Tested    to Aspirin                                    Compound Tested                                                                              Rats   Mg/rat    (Aspirin=1)                                   ______________________________________                                        d 2-(6'-methoxy-                                                                             40     0.2 and 0.6                                                                             22                                            2'-naphthyl)pro-                                                              pionic acid                                                                   d and 1 2-(6'-chloro-                                                                        10     0.2 and 0.6                                                                              5                                            2'-naphthyl)pro-                                                              pionic acid                                                                   the sodium salt of d                                                                         20     0.2 and 0.6                                                                             20                                            2-(6'-methoxy-2'                                                              naphthyl)-propionic acid                                                      ______________________________________                                    

EXAMPLE 40

The analgesic activity of the following2-(6'-substituted-2'-naphthyl)propionic acid derivatives was comparedwith that of aspirin. The test used was a mouse writhing test, whichconsists or orally administering the compound to be tested by gavage inan aqueous vehicle at time 0 to 18-20 gram male Swiss-Webster mice.Twenty minutes later 0.25 ml. of a 0.02% solution of phenylquinone(which is prepared by dissolving 4 mg. of phenylquinone in 0.5 ml.absolute ethanol, and adding the ethanol solution to 19.5 ml. warmeddistilled water) is injected intraperitoneally. This solution induceswrithing.

End point: the total number of mice that writhe and the average numberof writhes per mouse.

The degree of analgesic activity was measured as the difference in theaverage number of writhes between the control animals (animals receivingby gavage an aqueous vehicle with no compound) and the tested animals(animals receiving the compound to be tested). The results are shown inthe following table:

                  Table III                                                       ______________________________________                                                                       Activity compared                                           No. of            to Aspirin                                     Compound     rats    Total Dose                                                                              (Aspirin=1)                                    ______________________________________                                        d 2-(6'-methoxy-2'-                                                                        154     0.006-.384                                                                              8                                              naphthyl)propionic                                                            acid                                                                          the sodium salt of d                                                                       80      .048-.384 5                                              2-(6'-methoxy-2'-                                                             naphthyl)propionic                                                            acid                                                                          2-(6'-chloro-2'-                                                                           60      0.006-0.9 5                                              naphthyl)propionic                                                            acid                                                                          ______________________________________                                    

EXAMPLE 41

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        calcium di[d 2-(6'-methoxy                                                                      10                                                          2'-naphthyl)propionate]                                                       cornstarch        200                                                         sucrose           40                                                          ______________________________________                                    

The above ingredients are thoroughly mixed and pressed into singlescored tablets.

EXAMPLE 42

    ______________________________________                                        Ingredients        Quantity per tablet, mgs.                                  ______________________________________                                        d 2-(6'-methoxy-2'-naphthyl)-                                                                    5                                                          propionic acid                                                                cornstarch         100                                                        lactose            393                                                        magnesium stearate 2                                                          ______________________________________                                    

The above ingredients are mixed intimately and pressed into singlescored tablets.

EXAMPLE 43

    ______________________________________                                        Ingredients      Quantity per capsule, mgs.                                   ______________________________________                                        the potassium salt of                                                                          60                                                           dl 2-(6'-methyl-2'-                                                           naphthyl)propionic acid                                                       lactose          190                                                          ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

EXAMPLE 44

    ______________________________________                                        Ingredients       Quantity per capsule, mgs.                                  ______________________________________                                        the sodium salt of d 2-(6'-                                                                     60                                                          methoxy-2'-naphthyl)propionic                                                 acid                                                                          lactose           182                                                         magnesium stearate                                                                              8                                                           ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

EXAMPLE 45

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        2-(6-methoxy-2-naphthyl)-                                                                       30                                                          propionic acid                                                                cornstarch        100                                                         lactose           370                                                         Magnesium stearate                                                                              2                                                           ______________________________________                                    

The above ingredients are mixed intimately and pressed into singlescored tablets.

EXAMPLE 46

    ______________________________________                                        Ingredients       Quantity per capsule, mgs.                                  ______________________________________                                        2-(6-methylthio-2-naphthyl)-                                                                    25                                                          propionic acid                                                                lactose           225                                                         ______________________________________                                    

The above ingredients are mixed and introduced into a No. 1 hard-shellgelatin capsule.

In a similar manner as that described in each of the preceding threeexamples, the following compounds can also be so formulated:2-(6-methoxy-2-naphthyl)propionic acid,2-(6-methylthio-2-naphthyl)propionic acid,2-(6-chloro-2-naphthyl)propionic acid, 2-(6-fluoro-2-naphthyl)propionicacetic acid, 2-(6-methyl-2-naphthyl)propionic acid,2-(6-trifluoromethyl-2-naphthyl)propionic acid,2-(6-difluoromethoxy-2-naphthyl)propionic acid,2-(6-methyl-2-naphthyl)acrylic acid, sodium2-(6-methoxy-2-naphthyl)propionate and the like.

EXAMPLE 47

The anti-pyretic activity of the following2-(6'-substituted-2'-naphthyl)acetic acid ester derivative was comparedto the anti-pyretic activity of aspirin according to the protocol setforth in Example 39. The result is shown in the following table:

                  Table IV                                                        ______________________________________                                                    No.                Relative Potency                                           of     Dose Range  to Aspirin                                     Compound Tested                                                                           Rats   Tested Mg/Rat                                                                             (Aspirin=1)                                    ______________________________________                                        ethyl ester of d                                                                             1.0 mg.     10                                                 2-(2'-methoxy-6'-                                                             naphthyl)propionic                                                            acid                                                                          ______________________________________                                    

EXAMPLE 48

The anti-inflammatory activity of the following2-(6'-substituted-2'-naphthyl)acetic acid ester derivatives was comparedwith that of phenylbutazone by means of the modified carageenin-inducedrat paw inflammation test identified in Example 38. The results areshown in the following table:

                  Table V                                                         ______________________________________                                                             Dose                                                                   No.    Range    Relative Potency                                              of     Tested   to phenylbutazone                               Compound Tested                                                                             Rats   Mg/Rat   (phenylbutazone=1)                              ______________________________________                                        Methyl ester of d                                                                           30     0.3 & 0.9                                                                              3                                               2-(6'-methoxy-2'-                                                             naphthyl)propionic                                                            acid                                                                          ethyl ester of d                                                                            30     0.3-0.9  2                                               2-(6'-methoxy-2'-                                                             naphthyl)propionic                                                            acid                                                                          isopentyl ester of d                                                                        30     0.3-10   10                                              2-(6'-methoxy-2'-                                                             naphthyl)propionic                                                            acid                                                                          hexadecyl ester of                                                                          30     0.5-4.5  1                                               d 2-(6'methoxy-2'-                                                            naphthyl)propionic                                                            acid                                                                          ______________________________________                                    

EXAMPLE 49

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        ethyl 2-(6'-methyl-2'-                                                                          5                                                           naphthyl)propionate                                                           sucrose           245                                                         ______________________________________                                    

The above ingredients are thoroughly mixed and processed into singlescored tablets, one tablet being administered every three to four hours.

EXAMPLE 50

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        isoamyl ester of d 2-                                                                           30                                                          (6'-methoxy-2'-naphthyl)                                                      propionic acid                                                                cornstarch        100                                                         lactose           368                                                         magnesium stearate                                                                              2                                                           ______________________________________                                    

The above ingredients are mixed intimately and pressed into singlescored tablets.

EXAMPLE 51

    ______________________________________                                        Ingredients       Quantity per capsule, mgs.                                  ______________________________________                                        palmityl 2-(6'-methyl-                                                                          15                                                          thio-2'-naphthyl)-                                                            propionate                                                                    lactose           225                                                         dectrose          10                                                          ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

EXAMPLE 52

    ______________________________________                                        Ingredients       Quantity per capsule, mgs.                                  ______________________________________                                        Isohexyl 2-(6'-methoxy-                                                                         1                                                           2'-naphthyl)-2,2-methylene                                                    acetate                                                                       lactose           99                                                          ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

EXAMPLE 53

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        Methyl ester of d 2-                                                                            60                                                          (6'-methoxy-2'-naphthyl)-                                                     propionic acid                                                                lactose           135                                                         magnesium stearate                                                                              5                                                           ______________________________________                                    

The above ingredients are mixed and pressed into single tablets.

EXAMPLE 54

A solution is prepared having 100 mg. of d2-(6-methoxy-2-naphthyl)propionic acid dissolved per ml. of normalsaline solution.

EXAMPLE 55-56

Example 54 is repeated except dl 2-(6-methoxy-2-naphthyl)propionic acidand l 2-(6-methoxy-2-naphthyl)propionic acid are respectivelysubstituted for the d 2-(6-methoxy-2-naphthyl)propionic acid of Example54.

EXAMPLE 57

Example 54 is repeated except the saline vehicle additionally contains0.1% Tween 80 (sorbitan monooleate polyoxyethylene; a product of AtlasChemical Industries, Inc.).

EXAMPLE 58

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        calcium di[d 2-(6-methoxy                                                                       300                                                         2-naphthyl)propionate]                                                        cornstarch (paste)                                                                              50                                                          Magnesium stearate                                                                              0.8                                                         lactose           to 500                                                      ______________________________________                                    

The above ingredients are thoroughly mixed and pressed into singlescored tablets.

EXAMPLE 59

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        d 2-(6-methoxy-2-naphthyl)-                                                                     250                                                         propionic acid                                                                cornstarch        38                                                          magnesium stearate                                                                              0.76                                                        polyvinylpyrrolidone                                                                            17                                                          lactose           to 380                                                      ______________________________________                                    

The above ingredients are mixed intimately and pressed into singlescored tablets.

EXAMPLE 60

    ______________________________________                                        Ingredients       Quantity per capsule, mgs.                                  ______________________________________                                        2-(6-methyl-2-naphthyl)-                                                                        250                                                         propionic acid                                                                cornstarch         38                                                         lactose           to 380                                                      ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shellgelatine capsule.

EXAMPLE 61

    ______________________________________                                        Ingredients       Quantity per capsule, mgs.                                  ______________________________________                                        The sodium salt of d 2-(6-                                                                      300                                                         methoxy-2-naphthyl)propionic                                                  acid                                                                          lactose            72                                                         magnesium stearate                                                                               8                                                          ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

EXAMPLE 62

An injectable solution buffered to a pH of 8.5 is prepared having thefollowing composition:

    ______________________________________                                        d 2-(6-methoxy-2-naphthyl)                                                                            2      g                                              propionic acid                                                                K.sub.2 HPO.sub.4 buffet (0.4 M solution)                                                             2      ml.                                            KOH (1N)                8.6    ml.                                            water (sterile)         to 20  ml.                                            ______________________________________                                    

EXAMPLE 63

A suppository totaling 2.8 grams is prepared having the followingcomposition:

    ______________________________________                                        d 2-(6-methoxy-2-naphthyl)-                                                                          150-500 mg.                                            propionic acid                                                                Witepsol H-15          balance                                                (triglycerides of saturated                                                   vegetable fatty acids; a                                                      product of Riches-Nelson, Inc.,                                               New York, N.Y.)                                                               ______________________________________                                    

EXAMPLE 64

An oral suspension for pediatric use is prepared having the followingcomposition:

    ______________________________________                                        d 2-(6-methoxy-2-naphthyl)propionic acid                                                                2.5     g.                                          fumaric acid              0.5     g.                                          sodium chloride           2.0     g.                                          methyl paraben            0.1     g.                                          granulated sugar          25.5    g.                                          sorbitol (70% solution)   12.85   g.                                          Veegum K (Vanderbilt Co.) 1.0     g.                                          flavoring                 0.035   ml.                                         colorings                 0.5     mg.                                         distilled water           to 100  ml.                                         ______________________________________                                    

EXAMPLES 65-66

Powdered top dressings for veterinary use are prepared having thefollowing compositions:

    ______________________________________                                                             Ex. 65 Ex. 66                                            ______________________________________                                        d 2-(6-methoxy-2-naphthyl)propionic acid                                                             2.0 g.   4.0 g.                                        sucrose                5.7 g.   3.7 g.                                        polyvinyl pyrrolidone  0.3 g.   0.3 g.                                        ______________________________________                                    

EXAMPLE 67

A suppository totaling 2.8 grams is prepared having the followingcomposition:

    ______________________________________                                        the sodium salt of d 2-(6-                                                                           275 mg.                                                methoxy-2-naphthyl)-                                                          propionic acid                                                                Witepsol H-15          balance                                                ______________________________________                                    

EXAMPLE 68

    ______________________________________                                        Ingredients       Quantity per tablet, wt.%                                   ______________________________________                                        the sodium salt of d 2-(6-                                                                       68-75%                                                     methoxy-2-naphthyl)-                                                          propionic acid                                                                Avicel (FMC Corp.)                                                                               15-28%                                                     Cabosil (Cabot Corp.)                                                                            0.5-1%                                                     magnesium stearate                                                                               0.5-2%                                                     lactose             0-15%                                                     ______________________________________                                    

The above ingredients are thoroughy mixed and pressed into single scored400 mg. tablets.

What is claimed is:
 1. A composition for treating inflammation, pain orpyrexia in mammals comprising a pharmaceutically acceptacle non-toxicexcipient and a therapeutically effective amount of the isopentyl esterof d 2-(6'-methoxy-2'-naphthyl)propionic acid.
 2. A method of treatinginflammation, pain or pyrexia in mammals which comprises administeringto a mammal suffering therefrom a therapeutically effective amount ofthe isopentyl ester of d 2-(6'-methoxy-2'-naphthyl)propionic acid.
 3. Acomposition for treating inflammation, pain or pyrexia in mammalscomprising a pharmaceutically acceptable non-toxic excipient and atherapeutically effective amount of the methyl ester of d2-(6'-methoxy-2'-naphthyl)propionic acid.
 4. A method of treatinginflammation, pain or pyrexia in mammals which comprises administeringto a mammal suffering therefrom a therapeutically effective amount ofthe methyl ester of d 2-(6'-methoxy-2'-naphthyl)propionic acid.